Heterocyclic compound and use thereof

ABSTRACT

Compounds represented by the formulas 
                         
wherein each symbol is as defined in the specification, and a prodrug thereof have a superior renin inhibitory activity, and are useful as agents for the prophylaxis or treatment of hypertension, various organ damages attributable to hypertension and the like.

This application is a divisional application of U.S. application Ser.No. 12/999,428, filed Dec. 16, 2010 now U.S. Pat. No. 8,466,282, nowpending, which is the national phase filing of International PatentApplication No. PCT/JP2009/061438, filed Jun. 17, 2009.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a heterocyclic compound and the like,which has a superior renin inhibitory activity and is useful as an agentfor the prophylaxis or treatment of hypertension, various organ damagesattributable to hypertension, and the like.

BACKGROUND OF THE INVENTION

Hypertension is one of representative lifestyle-related diseases.Hypertension which is left untreated for long time lays a heavy burdenon the cardiovascular system and results in arteriosclerosis toprogress, thus causing various disorders in important organs, such ascerebral hemorrhage, cerebral infarction, cardiac failure, anginapectoris, myocardial infarction, renal failure and the like.Accordingly, the purpose of treating hypertension lies not only inlowering the blood pressure, but also in improving and/or preventingdisorders in important organs including brain, heart and kidney, bycontrolling the blood pressure. As a method of treating hypertension,there are available fundamental treatments based on improvement in thelifestyle, such as dietetic therapy, exercise therapy and the like, aswell as an attempt to control the blood pressure by positivepharmaceutical intervention.

The renin-angiotensin (RA) system is a system of biosynthesis ofangiotensin II (AII), which is a major vasopressor factor, and takes animportant role in the control of the blood pressure and the amount ofbody fluid. AII exhibits a strong vasoconstrictive effect brought by theintervention of AII receptors on the cellular membrane, thus raising theblood pressure, and also promotes cellular propagation or production ofextracellular matrix by directly acting on the AII receptors in thecardiac cells or renal cells. Therefore, drugs inhibiting increase inthe activity of the RA system can be expected to have a blood pressurelowering action as well as a powerful organ protecting action, and thusactive researches on such drugs have been conducted so far.

The method of inhibiting the AII action is broadly classified intomethods of inhibiting the biosynthesis of AII and methods of inhibitingthe binding of AII to AII receptors. For the drugs inhibiting thebiosynthesis of AII, angiotensin converting enzyme (ACE) inhibitorydrugs have been already put to practical use and are being confirmed tohave a blood pressure lowering action as well as an effect forprotecting various organs. However, since ACE is an enzyme identical tokininase II, which is a bradykinin degrading enzyme, ACE inhibitory druginhibits the biosynthesis of AII as well as the degradation ofbradykinin. As a result, ACE inhibitory drugs are believed to induceside effects such as dry cough, angioedema and the like, which areconsidered to be caused by accumulation of bradykinin.

As the drugs inhibiting the binding of AII to AII receptors, AII type 1receptor blockers (ARB) have been developed. ARB has a merit in that itcan inhibit, at the receptor level, the action of AII that isbiosynthesized by not only ACE but also an enzyme other than ACE, suchas chymase and the like. It is known that administration of ACEinhibitors and ARB increases the plasma renin activity (PRA) as acompensatory feedback effect, since these drugs act on a more peripheralregion of the RA system.

Renin is an enzyme occupying a position at the uppermost stream of theRA system, and converts angiotensinogen to angiotensin I. A renininhibitory drug inhibits the RA system by inhibiting the biosynthesis ofAII in the same manner as the ACE inhibitory drugs do, and thus can beexpected to have a blood pressure lowering action or an effect ofprotecting various organs. Since the renin inhibitory drug does not haveinfluence on the metabolism of bradykinin, it is believed to have norisk of side effects, such as dry cough and the like, that are observedwith the ACE inhibitory drugs. Furthermore, while the ACE inhibitorydrugs or ARB increase the PRA level, the renin inhibitory drugs are theonly drugs that can reduce PRA.

As renin inhibitors, orally administrable Aliskiren has been reported(Chem. Biol., 2000, vol. 7, pages 493-504; Hypertension, 2003, vol. 42,pages 1137-1143; J. Hypertens., 2005, vol. 23, pages 417-426 etc.).

As other renin inhibitors, the following compounds have been reported.

(1) A compound represented by the formula

wherein G is any one of groups represented by the following formulas (a)to (c)

R^(1a) is an optionally substituted C₁₋₆ alkyl group, an optionallysubstituted C₂₋₆ alkenyl group, an optionally substituted C₂₋₆ alkynylgroup, an optionally substituted C₃₋₁₀ cycloalkyl group, an optionallysubstituted C₅₋₆ cycloalkenyl group or an optionally substituted5-membered to 10-membered monocyclic or polycyclic heteroaryl-C₁₋₄ alkylgroup;R^(1b), R^(1c), R^(1d) and R^(1e) are the same or different and eachindependently is a hydrogen atom, a halogen atom, a hydroxyl group, aformyl group, a carboxy group, a cyano group, an optionally substitutedC₁₋₆ alkyl group, an optionally substituted C₂₋₆ alkenyl group, anoptionally substituted C₂₋₆ alkynyl group, an optionally substitutedC₃₋₁₀ cycloalkyl group, an optionally substituted C₅₋₆ cycloalkenylgroup, an optionally substituted C₆₋₁₀ aryl group, an optionallysubstituted C₇₋₁₄ aralkyl group, an optionally substituted 5-membered to10-membered monocyclic or polycyclic heteroaryl group, an optionallysubstituted 5-membered to 10-membered monocyclic or polycyclicheteroaryl C₁₋₄ alkyl group, an optionally substituted saturatedheterocyclic group, an optionally substituted C₁₋₆ alkylthio group, anoptionally substituted C₁₋₆ alkylsulfinyl group, an optionallysubstituted C₁₋₆ alkylsulfonyl group, an optionally substituted C₆₋₁₀arylthio group, an optionally substituted C₆₋₁₀ arylsulfinyl group, anoptionally substituted C₆₋₁₀ arylsulfonyl group, an optionallysubstituted C₁₋₆ alkoxy group, an optionally substituted C₃₋₆ alkynyloxygroup, an optionally substituted C₃₋₆ cycloalkyloxy group, an optionallysubstituted C₆₋₁₀ aryloxy group, an optionally substituted C₇₋₁₄aralkyloxy group, an optionally substituted 5-membered to 10-memberedmonocyclic or polycyclic heteroaryloxy group, an optionally substituted5-membered to 10-membered monocyclic or polycyclic heteroaryl C₁₋₄alkyloxy group, an optionally substituted amino group, an optionallysubstituted aminocarbonyl group, an optionally substitutedaminocarbonyloxy group, an optionally substituted aminosulfonyl group,an optionally substituted C₁₋₆ alkoxycarbonyl group, an optionallysubstituted C₃₋₆ cycloalkyloxycarbonyl group, an optionally substitutedC₁₋₄ alkylcarbonyl group, an optionally substituted C₃₋₆cycloalkylcarbonyl group, an optionally substituted C₆₋₁₀ arylcarbonylgroup or an optionally substituted 5-membered to 10-membered monocyclicor polycyclic heteroarylcarbonyl group; R^(1f) is a hydrogen atom, ahalogen atom, a hydroxyl group, a cyano group, an optionally substitutedC₁₋₆ alkyl group, an optionally substituted C₂₋₆ alkenyl group, anoptionally substituted C₂₋₆ alkynyl group, an optionally substitutedC₃₋₁₀ cycloalkyl group, an optionally substituted C₅₋₆ cycloalkenylgroup, an optionally substituted C₆₋₁₀ aryl group, an optionallysubstituted C₇₋₁₄ aralkyl group, an optionally substituted 5-membered to10-membered monocyclic or polycyclic heteroaryl group, an optionallysubstituted 5-membered to 10-membered monocyclic or polycyclicheteroaryl C₁₋₄ alkyl group, an optionally substituted saturatedheterocyclic group, an optionally substituted C₁₋₆ alkylthio group, anoptionally substituted C₁₋₆ alkylsulfinyl group, an optionallysubstituted C₁₋₆ alkylsulfonyl group, an optionally substituted C₁₋₆alkoxy group, an optionally substituted C₃₋₆ alkynyloxy group, anoptionally substituted C₃₋₆ cycloalkyloxy group, an optionallysubstituted C₆₋₁₀ aryloxy group, an optionally substituted C₇₋₁₄aralkyloxy group, an optionally substituted 5-membered to 10-memberedmonocyclic or polycyclic heteroaryl C₁₋₄ alkyloxy group, an optionallysubstituted amino group, an optionally substituted aminocarbonyl group,an optionally substituted aminosulfonyl group, an optionally substitutedC₁₋₄ alkoxycarbonyl group, an optionally substituted C₃₋₆cycloalkyloxycarbonyl group, an optionally substituted C₁₋₄alkylcarbonyl group, an optionally substituted C₃₋₆ cycloalkylcarbonylgroup, an optionally substituted C₆₋₁₀ arylcarbonyl group or anoptionally substituted 5-membered to 10-membered monocyclic orpolycyclic heteroarylcarbonyl group; R² is an optionally substitutedC₁₋₆ alkyl group, an optionally substituted C₂₋₆ alkenyl group, anoptionally substituted C₂₋₆ alkynyl group, an optionally substitutedC₃₋₆ cycloalkyl group, an optionally substituted C₅₋₆ cycloalkenylgroup, an optionally substituted C₆₋₁₀ aryl group, an optionallysubstituted C₇₋₁₄ aralkyl group or an optionally substituted 5-memberedto 10-membered monocyclic or polycyclic heteroaryl group;R^(3a), R^(3b), R^(3c) and R^(3d) are the same or different and eachindependently is a halogen atom, a cyano group or a group: -A-B (whereinA is a single bond, —(CH₂)_(S)0-, —(CH₂)_(S)N(R⁴)—, —(CH₂)_(S)SO₂—,—(CH₂)_(S)CO—, —(CH₂)_(S)COO—, —(CH₂)_(S)N(R⁴) CO—, —(CH₂)_(S)N(R⁴)SO₂—,—(CH₂)_(S)N(R⁴)COO—, —(CH₂)_(S)OCON(R⁴)—(CH₂)_(S)O—CO—,—(CH₂)_(S)N(R⁴)—, —(CH₂)_(S)N(R⁴)CON(R⁴)— or —(CH₂)_(S)SO₂N(R⁴)—, B is ahydrogen atom, an optionally substituted C₁₋₆ alkyl group, an optionallysubstituted C₂₋₆ alkenyl group, an optionally substituted C₂₋₆ alkynylgroup, an optionally substituted C₃₋₆ cycloalkyl group, an optionallysubstituted C₅₋₆ cycloalkenyl group, an optionally substituted C₆₋₁₀aryl group, an optionally substituted C₇₋₁₄ aralkyl group, an optionallysubstituted 5-membered to 10-membered monocyclic or polycyclicheteroaryl group, an optionally substituted 5-membered to 10-memberedmonocyclic or polycyclic heteroaryl C₁₋₄ alkyl group or an optionallysubstituted 5-membered or 6-membered saturated heterocyclic group (whenA is —(CH₂)_(S)N(R⁴)—, —(CH₂)_(S)OCON(R⁴)—, —(CH₂)_(S)CON(R⁴)—,—(CH₂)_(S)N(R⁴)CON(R⁴)— or —(CH₂)₆SO₂N(R⁴)—, R⁴ and B may be bonded toeach other to form a ring)), or two of R^(3a), R^(3b), R^(3c) and R^(3d)are hydrogen atoms, and the other two are bonded to each other to form abridged ring together with the hetero ring;R⁴ is a hydrogen atom, an optionally substituted C₁₋₆ alkyl group, anoptionally substituted C₃₋₆ cycloalkyl group, an optionally substitutedC₆₋₁₀ aryl group, an optionally substituted C₇₋₁₄ aralkyl group or anoptionally substituted 5-membered to 10-membered monocyclic orpolycyclic heteroaryl group;s is 0, 1 or 2 (when A is —(CH₂)_(S)N(R⁴)—, s is 0 or 2, and when A is—(CH₂)_(S)CON(R⁴)—, s is 1 or 2); andn is 0, 1 or 2, or a salt thereof (see WO2009/14217).(2) A compound represented by the formula

wherein R^(1a) is an optionally substituted C₁₋₆ alkyl group, anoptionally substituted C₂₋₁₀ alkenyl group, an optionally substitutedC₂₋₆ alkynyl group, an optionally substituted C₃₋₆ cycloalkyl group, anoptionally substituted C₅₋₆ cycloalkenyl group, an optionallysubstituted C₁₋₆ alkylsulfinyl group, an optionally substituted C₁₋₆alkylsulfonyl group, an optionally substituted aminocarbonyl group, anoptionally substituted C₁₋₄ alkoxycarbonyl group or an optionallysubstituted C₁₋₄ alkylcarbonyl group;R^(1b) and R^(1e) are the same or different and each independently is ahydrogen atom, a halogen atom, a cyano group, an optionally substitutedC₁₋₆ alkyl group, an optionally substituted C₁₋₆ alkoxy group, anoptionally substituted C₃₋₆ cycloalkyloxy group or an optionallysubstituted aminocarbonyl group;R^(1c) and R^(1d) are the same or different and each independently is ahydrogen atom, a halogen atom, a hydroxyl group, a formyl group, acarboxy group, a cyano group, an optionally substituted C₁₋₆ alkylgroup, an optionally substituted C₂₋₆ alkenyl group, an optionallysubstituted C₂₋₆ alkynyl group, an optionally substituted C₃₋₁₀cycloalkyl group, an optionally substituted C₅₋₆ cycloalkenyl group, anoptionally substituted C₆₋₁₀ aryl group, an optionally substituted C₇₋₁₄aralkyl group, an optionally substituted 5-membered to 10-memberedmonocyclic or polycyclic heteroaryl group, an optionally substituted5-membered to 10-membered monocyclic or polycyclic heteroaryl C₁₋₄ alkylgroup, an optionally substituted saturated heterocyclic group, anoptionally substituted C₁₋₆ alkylthio group, an optionally substitutedC₁₋₆ alkylsulfinyl group, an optionally substituted C₁₋₆ alkylsulfonylgroup, an optionally substituted C₆₋₁₀ arylthio group, an optionallysubstituted C₆₋₁₀ arylsulfinyl group, an optionally substituted C₆₋₁₀arylsulfonyl group, an optionally substituted C₁₋₆ alkoxy group, anoptionally substituted C₃₋₆ alkynyloxy group, an optionally substitutedC₃₋₁₀ cycloalkyloxy group, an optionally substituted C₆₋₁₀ aryloxygroup, an optionally substituted C₇₋₁₄ aralkyloxy group, an optionallysubstituted 5-membered to 10-membered monocyclic or polycyclicheteroaryloxy group, an optionally substituted 5-membered to 10-memberedmonocyclic or polycyclic heteroaryl C₁₋₄ alkyloxy group, an optionallysubstituted amino group, an optionally substituted aminocarbonyl group,an optionally substituted aminosulfonyl group, an optionally substitutedC₁₋₄ alkoxycarbonyl group, an optionally substituted C₃₋₆cycloalkyloxycarbonyl group, an optionally substituted C₁₋₄alkylcarbonyl group, an optionally substituted C₃₋₆ cycloalkylcarbonylgroup, an optionally substituted C₆₋₁₀ arylcarbonyl group or anoptionally substituted 5-membered to 10-membered monocyclic orpolycyclic heteroarylcarbonyl group; R^(1f) are the same or differentand each independently is a hydrogen atom, a halogen atom, a cyanogroup, an optionally substituted C₁₋₆ alkyl group, an optionallysubstituted C₁₋₆ alkoxy group, an optionally substituted C₃₋₁₀cycloalkyl group, an optionally substituted C₂₋₆ alkenyl group, anoptionally substituted C₂₋₆ alkenyloxy group, an optionally substitutedC₃₋₆ alkynyl group, an optionally substituted C₃₋₆ alkynyloxy group oran optionally substituted C₃₋₁₀ cycloalkyloxy group;R² is an optionally substituted C₁₋₆ alkyl group, an optionallysubstituted C₂₋₆ alkenyl group, an optionally substituted C₂₋₆ alkynylgroup, an optionally substituted C₃₋₁₀ cycloalkyl group, an optionallysubstituted C₅₋₆ cycloalkenyl group, an optionally substituted C₆₋₁₀aryl group, an optionally substituted C₇₋₁₄ aralkyl group or anoptionally substituted 5-membered to 10-membered monocyclic orpolycyclic heteroaryl group;R^(3a), R^(3b), R^(3c) and R^(3d) are the same or different and eachindependently is a halogen atom, a cyano group or a group: -A-B (whereinA is a single bond, —(CH₂)_(S)0-, —(CH₂)_(S)N(R⁴)—, —(CH₂)_(S)SO₂—,—(CH₂)_(S)CO—, —(CH₂)_(S)COO—, —(CH₂)_(S)N(R⁴) CO—, —(CH₂)_(S)N(R⁴)SO₂—,—(CH₂)_(S)N(R⁴)COO—, —(CH₂)_(S)OCON(R⁴)—, —(CH₂)_(S)O—CO—,—(CH₂)_(S)ON(R⁴)—, —(CH₂)_(S)N(R⁴)CON(R⁴)— or —(CH₂)_(S)SO₂N(R⁴)—,B is a hydrogen atom, an optionally substituted C₁₋₆ alkyl group, anoptionally substituted C₂₋₆ alkenyl group, an optionally substitutedC₂₋₆ alkynyl group, an optionally substituted C₃₋₆ cycloalkyl group, anoptionally substituted C₅₋₆ cycloalkenyl group, an optionallysubstituted C₆₋₁₀ aryl group, an optionally substituted C₇₋₁₄ aralkylgroup, an optionally substituted 5-membered to 10-membered monocyclic orpolycyclic heteroaryl group, an optionally substituted 5-membered to10-membered monocyclic or polycyclic heteroaryl C₁₋₄ alkyl group or anoptionally substituted saturated heterocyclic group (when A is—(CH₂)_(S)N(R⁴)—, —(CH₂)_(S)OCON(R⁴)—, —(CH₂)_(S)CON(R⁴)—,—(CH₂)_(S)N(R⁴)CON(R⁴)— or —(CH₂)_(S)SO₂N(R⁴)—, R⁴ and B may be bondedto each other to form a ring)), or two of R^(3a), R^(3b), R^(3c) andR^(3d) are hydrogen atoms, and the other two are bonded to each other toform a bridged ring together with the hetero ring;R⁴ is a hydrogen atom, an optionally substituted C₁₋₆ alkyl group, anoptionally substituted C₃₋₆ cycloalkyl group, an optionally substitutedC₆₋₁₀ aryl group, an optionally substituted C₇₋₁₄ aralkyl group or anoptionally substituted 5-membered to 10-membered monocyclic or apolycyclic heteroaryl group;s is 0, 1 or 2 (when A is —(CH₂)_(S)N(R⁴)—, s is 0 or 2, and when A is—(CH₂)_(S)CON(R⁴)—, s is 1 or 2); andn is 0, 1 or 2, or a salt thereof (see WO2009/05002).(3) A compound represented by the formula

wherein

R¹ is a substituent;

R² is a cyclic group optionally having substituent(s), a C₁₋₁₀ alkyloptionally having substituent(s), a C₂₋₁₀ alkenyl optionally havingsubstituent(s) or a C₂₋₁₀ alkynyl optionally having substituent(s);

R³ is a hydrogen atom, a halogen atom, a C₁₋₆ alkyl or C₁₋₆ alkoxy;

ring A is a nitrogen-containing heterocycle optionally havingsubstituent(s); and

ring B is a piperazine optionally further having substituent(s) besidesR¹, or a salt thereof (see WO2009/001915).

(4) A compound represented by the formula

wherein R¹ is A) an alkyl group substituted by the group selectedfrom 1) an optionally substituted alkoxy group, 2) a hydroxyl group, 3)a halogen atom, 4) an optionally substituted aryl group, 5) anoptionally substituted tetrahydronaphthyl group, 6) an optionallysubstituted indolyl group, 7) an optionally substituted benzofuranylgroup, 8) an optionally substituted benzothienyl group, 9) an optionallysubstituted quinolyl group, 10) an optionally substituteddihydrochromenyl group, 11) an optionally substituteddihydrobenzofuranyl group, 12) an optionally substituted indazolylgroup, 13) an optionally substituted pyrrolopyridinyl group, 14) anoptionally substituted benzoxazinyl group, 15) an optionally substitutedxanthenyl group, 16) an optionally substituted indolinyl group and 17)an optionally substituted imidazopyridinyl group, B) an optionallysubstituted aryl group, C) an optionally substituted heterocyclic group,D) a cycloalkyl group or E) an alkyl group,R² is A) an alkyl group substituted by the group selected from 1) anoptionally substituted alkoxy group, 2) a hydroxyl group, 3) a halogenatom, 4) an optionally substituted aryl group, 5) an optionallysubstituted tetrahydronaphthyl group, 6) an optionally substitutedindolyl group, 7) an optionally substituted benzofuranyl group, 8) anoptionally substituted benzothienyl group, 9) an optionally substitutedquinolyl group, 10) an optionally substituted dihydrochromenyl group,11) an optionally substituted dihydrobenzofuranyl group, 12) anoptionally substituted indazolyl group, 13) an optionally substitutedpyrrolopyridinyl group, 14) an optionally substituted benzoxazinylgroup, 15) an optionally substituted xanthenyl group, 16) an optionallysubstituted indolinyl group and 17) an optionally substitutedimidazopyridinyl group, B) an optionally substituted aryl group, C) anoptionally substituted heterocyclic group, D) an optionally substitutedalkylcarbonyl group, E) an optionally substituted arylcarbonyl group, F)an optionally substituted heterocyclic group-substituted carbonyl groupor G) a cycloalkylcarbonyl group, T is a methylene group or a carbonylgroup, andR³, R⁴, R⁵ and R⁶ are the same or different and each is a hydrogen atom,an optionally substituted carbamoyl group or an optionally a substitutedalkyl group, or a salt thereof (see WO2008/153182).(5) A compound represented by the formula

wherein R^(1a) is an optionally substituted C₁₋₆ alkyl group, a C₃₋₆cycloalkyl group substituted by C₁₋₄ alkoxy, an optionally substitutedC₂₋₆ alkenyl group, an optionally substituted C₂₋₆ alkenyloxy group, anoptionally substituted C₃₋₆ alkynyl group, an optionally substitutedC₃₋₆ alkynyloxy group, an optionally substituted C₁₋₆ alkylsulfinylgroup, an optionally substituted C₁₋₆ alkylsulfonyl group, an optionallysubstituted C₁₋₆ alkoxy group, an optionally substituted amino group, anoptionally substituted aminocarbonyl group, an optionally substitutedC₁₋₄ alkoxycarbonyl group or an optionally substituted C₁₋₄alkylcarbonyl group;R^(1b) and R^(1e) are each a hydrogen atom, a halogen atom, a cyanogroup, an optionally substituted C₁₋₆ alkyl group, an optionallysubstituted C₁₋₆ alkoxy group, an optionally substituted C₃₋₆cycloalkyloxy group or an optionally substituted aminocarbonyl group;R^(1c) and R^(1d) are the same or different and each independently is ahydrogen atom, a halogen atom, a hydroxyl group, a formyl group, acarboxy group, a cyano group, an optionally substituted C₁₋₆ alkylgroup, an optionally substituted C₂₋₆ alkenyl group, an optionallysubstituted C₂₋₆ alkynyl group, an optionally substituted C₃₋₁₀cycloalkyl group, an optionally substituted C₅₋₆ cycloalkenyl group, anoptionally substituted C₆₋₁₀ aryl group, an optionally substituted C₇₋₁₄aralkyl group, an optionally substituted 5-membered to 10-memberedmonocyclic or polycyclic heteroaryl group, an optionally substituted5-membered to 10-membered monocyclic or polycyclic heteroaryl C₁₋₄ alkylgroup, an optionally substituted saturated heterocyclic group, anoptionally substituted C₁₋₆ alkylthio group, an optionally substitutedC₁₋₆ alkylsulfinyl group, an optionally substituted C₁₋₆ alkylsulfonylgroup, an optionally substituted C₆₋₁₀ arylthio group, an optionallysubstituted C₆₋₁₀ arylsulfinyl group, an optionally substituted C₆₋₁₀arylsulfonyl group, an optionally substituted C₁₋₆ alkoxy group, anoptionally substituted C₃₋₆ alkynyloxy group, an optionally substitutedC₃₋₁₀ cycloalkyloxy group, an optionally substituted C₆₋₁₀ aryloxygroup, an optionally substituted C₇₋₁₄ aralkyloxy group, an optionallysubstituted 5-membered to 10-membered monocyclic or polycyclicheteroaryloxy group, an optionally substituted 5-membered to 10-memberedmonocyclic or polycyclic heteroaryl C₁₋₄ alkyloxy group, an optionallysubstituted amino group, an optionally substituted aminocarbonyl group,an optionally substituted aminosulfonyl group, an optionally substitutedC₁₋₄ alkoxycarbonyl group, an optionally substituted C₃₋₁₀cycloalkyloxycarbonyl group, an optionally substituted C₁₋₄alkylcarbonyl group, an optionally substituted C₃₋₁₀ cycloalkylcarbonylgroup, an optionally substituted C₆₋₁₀ arylcarbonyl group or anoptionally substituted 5-membered to 10-membered monocyclic orpolycyclic heteroarylcarbonyl group; R^(1f) and R^(1g) are the same ordifferent and each independently is a hydrogen atom, a halogen atom, acyano group, an optionally substituted C₁₋₆ alkyl group, an optionallysubstituted C₁₋₆ alkoxy group, an optionally substituted C₃₋₁₀cycloalkyl group, an optionally substituted C₂₋₆ alkenyl group, anoptionally substituted C₂₋₆ alkenyloxy group, an optionally substitutedC₃₋₆ alkynyl group, an optionally substituted C₃₋₆ alkynyloxy group oran optionally substituted C₃₋₁₀ cycloalkyloxy group;R² is an optionally substituted C₁₋₆ alkyl group, an optionallysubstituted C₂₋₆ alkenyl group, an optionally substituted C₂₋₆ alkynylgroup, an optionally substituted C₃₋₁₀ cycloalkyl group, an optionallysubstituted C₅₋₆ cycloalkenyl group, an optionally substituted C₆₋₁₀aryl group, an optionally substituted C₇₋₁₄ aralkyl group or anoptionally substituted 5-membered to 10-membered monocyclic orpolycyclic heteroaryl group;R^(3a), R^(3b), R^(3c) and R^(3d) are the same or different and eachindependently is a halogen atom, a cyano group or a group: -A-B (whereinA is a single bond, —(CH₂)_(S)0-, —(CH₂)_(S)N(R⁴)—, —(CH₂)_(S)SO₂—,—(CH₂)_(S)CO—, —(CH₂)_(S)COO—, —(CH₂)_(S)N(R⁴) CO—, —(CH₂)_(S)N(R⁴)SO₂—,—(CH₂)_(S)N(R⁴)COO—, —(CH₂)_(S)OCON(R⁴)—, —(CH₂)_(S)O—CO—,—(CH₂)_(S)ON(R⁴), —(CH₂)_(S)N(R⁴)CON(R⁴)— or —(CH₂)_(S)SO₂N(R⁴)—,B is a hydrogen atom, an optionally substituted C₁₋₆ alkyl group, anoptionally substituted C₂₋₆ alkenyl group, an optionally substitutedC₂₋₆ alkynyl group, an optionally substituted C₃₋₆ cycloalkyl group, anoptionally substituted C₅₋₆ cycloalkenyl group, an optionallysubstituted C₆₋₁₀ aryl group, an optionally substituted C₇₋₁₄ aralkylgroup, an optionally substituted 5-membered to 10-membered monocyclic orpolycyclic heteroaryl group, an optionally substituted 5-membered to10-membered monocyclic or polycyclic heteroaryl C₁₋₄ alkyl group or anoptionally substituted saturated heterocyclic group (when A is—(CH₂)_(S)N(R⁴)—, —(CH₂)_(S)OCON(R⁴)—, —(CH₂)_(S)CON(R⁴)—,—(CH₂)_(S)N(R⁴)CON(R⁴)— or —(CH₂)_(S)SO₂N(R⁴)—, R⁴ and B may be bondedto each other to form a ring)), or two of R^(3a), R^(3b), R^(3c) andR^(3d) are hydrogen atoms, and the other two are bonded to each other toform a bridged ring together with the hetero ring;R⁴ is a hydrogen atom, an optionally substituted C₁₋₆ alkyl group, anoptionally substituted C₃₋₆ cycloalkyl group, an optionally substitutedC₆₋₁₀ aryl group, an optionally substituted C₇₋₁₄ aralkyl group or anoptionally substituted 5-membered to 10-membered monocyclic or apolycyclic heteroaryl group;s is 0, 1 or 2 (when A is —(CH₂)_(S)N(R⁴)—, s is 0 or 2, and when A is—(CH₂)_(S)CON(R⁴)—, s is 1 or 2); andn is 0, 1 or 2, or a salt thereof (see WO2008/153135).(6) A compound represented by the formula

whereinR¹ is a substituent,R² is a cyclic group optionally having substituent(s), C₁₋₁₀ alkyloptionally having substituent(s), C₂₋₁₀ alkenyl optionally is havingsubstituent(s) or C₂₋₁₀ alkynyl optionally having substituent(s),R³ is a hydrogen atom, a halogen atom, C₁₋₆ alkyl or C₁₋₆ alkoxy,X is a bond or a spacer having 1 to 6 atoms in the main chain, ring A isa C₅₋₇ cycloalkane optionally having substituent(s), andring B is a piperazine optionally further having substituent(s) besidesR¹, or a salt thereof (see WO2008/139941).(7) A compound represented by the formula

wherein R¹ and R² are each a hydrocarbon group optionally havingsubstituent(s) or a heterocyclic group optionally having substituent(s),orR¹ and R² may form, together with the nitrogen atom bonded thereto, anitrogen-containing heterocycle optionally having substituent(s),R³ is a substituent,ring A is a homocycle optionally having substituent(s) or a heterocycleoptionally having substituent(s), or a salt thereof (see WO2009/051112).(8) A compound represented by the formula

wherein G is one group selected from the group consisting of thefollowing formulas (a) to (d)

wherein R^(1a) is an optionally substituted C₁₋₆ alkyl group, a C₃₋₆cycloalkoxy group substituted by C₁₋₄ alkoxy, an optionally substitutedC₂₋₆ alkenyl group, an optionally substituted C₂₋₆ alkenyloxy group, anoptionally substituted C₃₋₆ alkynyl group, an optionally substitutedC₃₋₆ alkynyloxy group, an optionally substituted C₁₋₆ alkylsulfinylgroup, an optionally substituted C₁₋₆ alkylsulfonyl group, an optionallysubstituted C₁₋₆ alkoxy group, an optionally substituted amino group, anoptionally substituted aminocarbonyl group, an optionally substitutedC₁₋₄ alkoxycarbonyl group or an optionally substituted C₁₋₄alkylcarbonyl group;

R^(1b) and R^(1e) are the same or different and each independently is ahydrogen atom, a cyano group, an optionally substituted C₁₋₈ alkylgroup, an optionally substituted C₁₋₆ alkoxy group, an optionallysubstituted C₂₋₆ alkenyl group, C₁₋₆ alkylsulfonyl group, or a halogenatom;R^(1c) and R^(1d) are the same or different and each independently is ahydrogen atom, a halogen atom, a hydroxyl group, a formyl group, acarboxy group, a cyano group, an optionally substituted C₁₋₆ alkylgroup, an optionally substituted C₂₋₆ alkenyl group, an optionallysubstituted C₂₋₆ alkynyl group, an optionally substituted C₃₋₁₀cycloalkyl group, an optionally substituted C₅₋₆ cycloalkenyl group, anoptionally substituted C₆₋₁₀ aryl group, an optionally substituted C₇₋₁₄aralkyl group, an optionally substituted 5-membered to 10-memberedmonocyclic or polycyclic heteroaryl group, an optionally substituted5-membered or 6-membered saturated heterocyclic group, an optionallysubstituted C₁₋₆ alkylthio group, an optionally substituted C₁₋₆alkylsulfinyl group, an optionally substituted C₁₋₆ alkylsulfonyl group,an optionally substituted C₆₋₁₀ arylthio group, an optionallysubstituted C₆₋₁₀ arylsulfinyl group, an optionally substituted C₆₋₁₀arylsulfonyl group, an optionally substituted C₁₋₆ alkoxy group, anoptionally substituted C₃₋₆ alkynyloxy group, an optionally substitutedC₃₋₁₀ cycloalkyloxy group, an optionally substituted C₆₋₁₀ aryloxygroup, an optionally substituted C₇₋₁₄ aralkyloxy group, an optionallysubstituted 5-membered to 10-membered monocyclic or polycyclicheteroaryloxy group, an optionally substituted amino group, anoptionally substituted aminocarbonyl group, an optionally substitutedaminosulfonyl group, an optionally substituted C₁₋₄ alkoxycarbonylgroup, an optionally substituted C₃₋₁₀ cycloalkyloxycarbonyl group, anoptionally substituted C₁₋₄ alkylcarbonyl group, an optionallysubstituted C₃₋₁₀ cycloalkylcarbonyl group, an optionally substitutedC₆₋₁₀ arylcarbonyl group or an optionally substituted 5-membered to10-membered monocyclic or polycyclic heteroarylcarbonyl group;R^(1f) is a hydrogen atom, a halogen atom, a cyano group, an optionallysubstituted C₃₋₆ cycloalkyl group, an optionally substituted C₂₋₆alkenyl group, an optionally substituted C₂₋₆ alkenyloxy group, anoptionally substituted C₃₋₆ alkynyl group, an optionally substitutedC₃₋₆ alkynyloxy group, an optionally substituted C₃₋₁₀ cycloalkyloxygroup, an optionally substituted C₁₋₆ alkoxy group or an optionallysubstituted C₁₋₆ alkyl group;R² is an optionally substituted C₁₋₆ alkyl group, an optionallysubstituted C₂₋₆ alkenyl group, an optionally substituted C₂₋₆ alkynylgroup, an optionally substituted C₃₋₁₀ cycloalkyl group, an optionallysubstituted C₅₋₆ cycloalkenyl group, an optionally substituted C₆₋₁₀aryl group, an optionally substituted C₇₋₁₄ aralkyl group or anoptionally substituted 5-membered to 10-membered monocyclic orpolycyclic heteroaryl group;R^(3a), R^(3b), R^(3c) and R^(3d) are the same or different and eachindependently is a halogen atom, a hydroxyl group, a formyl group, acarboxy group, a cyano group or a group: -A-B (wherein A is a singlebond, —(CH₂)_(S)0-, —(CH₂)_(S)N(R⁴)—, —(CH₂)_(S)SO₂—, —(CH₂)_(S)CO—,—(CH₂)_(S)COO—, —(CH₂)_(S)N(R⁴)CO—, —(CH₂)_(S)N(R⁴)SO₂—,—(CH₂)_(S)N(R⁴)COO—, —(CH₂)_(S)OCON(R⁴)—, —(CH₂)_(S)O—CO—,—(CH₂)_(S)ON(R⁴)—, —(CH₂)_(S)N(R⁴)CON(R⁴)— or —(CH₂)_(S)SO₂N(R⁴)—,B is a hydrogen atom, an optionally substituted C₁₋₆ alkyl group, anoptionally substituted C₂₋₆ alkenyl group, an optionally substitutedC₂₋₆ alkynyl group, an optionally substituted C₃₋₁₀ cycloalkyl group, anoptionally substituted C₅₋₆ cycloalkenyl group, an optionallysubstituted C₆₋₁₀ aryl group, an optionally substituted C₇₋₁₄ aralkylgroup, an optionally substituted 5-membered to 10-membered monocyclic orpolycyclic heteroaryl group, an optionally substituted 5-membered to10-membered monocyclic or polycyclic heteroaryl C₁₋₄ alkyl group or anoptionally substituted 5-membered or 6-membered saturated heterocyclicgroup (when A is —(CH₂)_(S)N(R⁴)—, —(CH₂)_(S)OCON(R⁴)—,—(CH₂)_(S)CON(R⁴)—, —(CH₂)_(S)N(R⁴)CON(R⁴)— or —(CH₂)_(S)SO₂N(R⁴)—, R⁴and B may be bonded to each other to form a ring)), or two of R^(3a),R^(3b), R^(3c) and R^(3d) are hydrogen atoms, and the other two arebonded to each other to form a bridged ring together with the heteroring; R⁴ is a hydrogen atom, an optionally substituted C₁₋₆ alkyl group,an optionally substituted C₃₋₆ cycloalkyl group, an optionallysubstituted C₆₋₁₀ aryl group, an optionally substituted C₇₋₁₄ aralkylgroup or an optionally substituted 5-membered to 10-membered monocyclicor polycyclic heteroaryl group;s is 0, 1 or 2 (when A is —(CH₂)_(S)N(R⁴)—, s is 0 or 2, andwhen A is —(CH₂)_(S)CON(R⁴)—, s is 1 or 2); andn is 0, 1 or 2, or a salt thereof (see WO 2008/136457).(9) A compound represented by the formula

wherein R^(1a) is a hydrogen atom, a halogen atom, a hydroxyl group, aformyl group, a carboxy group, a cyano group, an optionally substitutedC₁₋₆ alkyl group, an optionally substituted C₂₋₆ alkenyl group, anoptionally substituted C₂₋₆ alkynyl group, an optionally substitutedC₃₋₆ cycloalkyl group, a C₁₋₆ alkylthio group, a C₁₋₆ alkylsulfonylgroup, a C₁₋₆ alkoxy group optionally substituted by a halogen atom,C₁₋₄ alkoxy or C₃₋₆ cycloalkyl, an optionally substituted C₃₋₆cycloalkoxy group, an optionally substituted amino group, aminocarbonylgroup, C₁₋₄ alkoxycarbonyl group, a C₁₋₄ alkylcarbonyl group, anoptionally substituted C₆₋₁₀ aryl group, an optionally substituted C₆₋₁₀aryloxy group or an optionally substituted C₇₋₁₄ aralkyloxy group;

R^(1b) is a C₁₋₆ alkyl group substituted by mono-C₁₋₆alkoxycarbonylamino, an optionally substituted C₁₋₆ alkylsulfinyl group,an optionally substituted C₁₋₆ alkylsulfonyl group, a substituted C₁₋₆alkoxy group, an optionally substituted amino group, an optionallysubstituted aminocarbonyl group, an optionally substituted C₁₋₄alkoxycarbonyl group or an optionally substituted C₁₋₄ alkylcarbonylgroup (wherein the substituted C₁₋₆ alkoxy group is substituted by onegroup selected from the group consisting of hydroxy, C₁₋₄ alkoxy, C₃₋₆cycloalkoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy,carboxy, mono-C₁₋₆ alkylcarbonylamino and mono-C₁₋₆alkoxycarbonylamino), R^(1c) is a hydrogen atom, a halogen atom, ahydroxyl group, a formyl group, a carboxy group, a cyano group, anoptionally substituted C₁₋₆ alkyl group, an optionally substituted C₃₋₆cycloalkyl group, an optionally substituted C₅₋₆ cycloalkenyl group, anoptionally substituted 5-membered or 6-membered saturated heterocyclicgroup, an optionally substituted C₁₋₆ alkylthio group, an optionallysubstituted C₁₋₆ alkylsulfinyl group, an optionally substituted C₁₋₆alkylsulfonyl group, an optionally substituted C₆₋₁₀ arylthio group, anoptionally substituted C₆₋₁₀ arylsulfinyl group, an optionallysubstituted C₆₋₁₀ arylsulfonyl group, an optionally substituted C₁₋₆alkoxy group, an optionally substituted C₃₋₆ cycloalkyloxy group, anoptionally substituted C₆₋₁₀ aryloxy group, an optionally substitutedC₇₋₁₄ aralkyloxy group, an optionally substituted amino group, anoptionally substituted aminocarbonyl group, an optionally substitutedC₁₋₄ alkoxycarbonyl group, an optionally substituted C₃₋₆cycloalkyloxycarbonyl group, an optionally substituted C₁₋₄alkylcarbonyl group, an optionally substituted C₃₋₆ cycloalkylcarbonylgroup, an optionally substituted C₆₋₁₀ arylcarbonyl group, an optionallysubstituted C₇₋₁₄ aralkyl group or an optionally substituted 5-memberedto 10-membered monocyclic or polycyclic heteroarylcarbonyl group, orR^(1a) is a hydrogen atom; R^(1b) and R^(1c) in combination form a fusedring together with the hetero ring, which contains at least one heteroatom;

R² is a hydrogen atom, an optionally substituted C₁₋₆ alkyl group, anoptionally substituted C₂₋₆ alkenyl group, an optionally substitutedC₂₋₆ alkynyl group, an optionally substituted C₃₋₁₀ cycloalkyl group, anoptionally substituted C₅₋₆ cycloalkenyl group, an optionallysubstituted C₁₋₁₀ aryl group, an optionally substituted C₇₋₁₄ aralkylgroup or an optionally substituted 5-membered to 10-membered monocyclicor polycyclic heteroaryl group (when R^(1a) is a C₁₋₆ alkoxy groupsubstituted by a halogen atom, R² is not a hydrogen atom);R^(3a), R^(3b), R^(3c) and R^(3d) are the same or different and eachindependently is a halogen atom, a cyano group or a group: -A-B (whereinA is a single bond, —(CH₂)_(S)O—, —(CH₂)_(S)N(R⁴)—, —(CH₂)_(S)SO₂—,—(CH₂)_(S)CO—, —(CH₂)_(S)COO—, —(CH₂)_(S)N(R⁴) CO—, —(CH₂)_(S)N(R⁴)SO₂—,—(CH₂)_(S)N(R⁴)COO—, —(CH₂)_(S)OCON(R⁴)—, —(CH₂)_(S)O—CO—,—(CH₂)_(S)CON(R⁴)—, —(CH₂)_(S)N(R⁴)CON(R⁴)— or —(CH₂)_(S)SO₂N(R⁴)—,B is a hydrogen atom, an optionally substituted C₁₋₆ alkyl group, anoptionally substituted C₂₋₆ alkenyl group, an optionally substitutedC₂₋₆ alkynyl group, an optionally substituted C₃₋₁₀ cycloalkyl group, anoptionally substituted C₅₋₆ cycloalkenyl group, an optionallysubstituted C₆₋₁₀ aryl group, an optionally substituted C₇₋₁₄ aralkylgroup, an optionally substituted 5-membered to 10-membered monocyclic orpolycyclic heteroaryl group, an optionally substituted 5-membered to10-membered monocyclic or polycyclic heteroaryl C₁₋₄ alkyl group or anoptionally substituted saturated heterocyclic group (when A is—(CH₂)_(S)N(R⁴)—, —(CH₂)_(S)OCON(R⁴)—, —(CH₂)_(S)CON(R⁴)—,—(CH₂)_(S)N(R⁴)CON(R⁴)— or —(CH₂)_(S)SO₂N(R⁴)—, R⁴ and B may be bondedto each other to form a ring)), or two of R^(3a), R^(3b), R^(3c) andR^(3d) are hydrogen atoms, and the other two are bonded to each other toform a bridged ring together with the hetero ring;R⁴ is a hydrogen atom, optionally substituted C₁₋₆ alkyl group, anoptionally substituted C₃₋₁₀ cycloalkyl group, an optionally substitutedC₆₋₁₀ aryl group, an optionally substituted C₇₋₁₄ aralkyl group or anoptionally substituted 5-membered to 10-membered monocyclic orpolycyclic heteroaryl group;s is 0, 1 or 2 (when A is —(CH₂)_(S)N(R⁴)—, s is 0 or 2, and when A is—(CH₂)_(S)CON(R⁴)—, s is 1 or 2); andn is 0, 1 or 2, or a salt thereof (see WO2008/093737).(10) A compound represented by the formula

wherein R1 is hydrogen, unsubstituted or substituted alkyl,unsubstituted or substituted alkenyl, unsubstituted or substitutedalkynyl, unsubstituted or substituted aryl, unsubstituted or substitutedheterocyclyl or unsubstituted or substituted cycloalkyl;R2 is unsubstituted or substituted alkyl, unsubstituted or substitutedalkenyl, unsubstituted or substituted alkynyl, unsubstituted orsubstituted aryl, unsubstituted or substituted heterocyclyl,unsubstituted or substituted cycloalkyl, or acyl;R3 is hydrogen, unsubstituted or substituted aryl or unsubstituted orsubstituted alkyl;R4 is unsubstituted or substituted alkyl, unsubstituted or substitutedalkenyl, unsubstituted or substituted alkynyl, unsubstituted orsubstituted aryl, unsubstituted or substituted heterocyclyl,unsubstituted or substituted cycloalkyl, or acyl;or R3 and R4 may form together a 3 to 7 membered nitrogen containingsaturated hydrocarbon ring which can be unsubstituted or substituted;R6 is hydrogen, halo, unsubstituted alkyl or unsubstituted alkoxy;R7 and R8 are independently of each other hydrogen or halo; andT is methylene or carbonyl; or a salt thereof (see WO2007/077005).(11) A compound represented by the formula

wherein R1 is hydrogen, unsubstituted or substituted alkyl,unsubstituted or substituted alkenyl, unsubstituted or substitutedalkynyl, unsubstituted or substituted aryl, unsubstituted or substitutedheterocyclyl or unsubstituted or substituted cycloalkyl;R2 is unsubstituted or substituted alkyl, unsubstituted or substitutedalkenyl, unsubstituted or substituted alkynyl, unsubstituted orsubstituted aryl, unsubstituted or substituted heterocyclyl,unsubstituted or substituted cycloalkyl, or acyl;R3 is hydrogen, unsubstituted or substituted aryl or unsubstituted orsubstituted alkyl,R4 is unsubstituted or substituted alkyl, unsubstituted or substitutedalkenyl, unsubstituted or substituted alkynyl, unsubstituted orsubstituted aryl, unsubstituted or substituted heterocyclyl,unsubstituted or substituted cycloalkyl, or acyl;or R3 and R4 may form together a 3 to 7 membered nitrogen containingsaturated hydrocarbon ring which can be unsubstituted or substituted;andT is methylene or carbonyl; or a salt thereof (see WO2007/006534).(12) A compound represented by the formula

whereinring A is a 5- or 6-membered aromatic heterocycle optionally havingsubstituent(s);U, V and W are each independently C or N, provided that when any one ofU, V and W is N, then the others should be C;Ra and Rb are each independently a cyclic group optionally havingsubstituent(s), a C₁₋₁₀ alkyl group optionally having substituent(s), aC₂₋₁₀ alkenyl group optionally having substituent(s), or a C₂₋₁₀ alkynylgroup optionally having substituent(s);X is a bond, or a spacer having 1 to 6 atoms in the main chain;Y is a spacer having 1 to 6 atoms in the main chain;Rc is a hydrocarbon group optionally containing heteroatom(s) as theconstituting atom(s), which optionally has substituent(s);m and n are each independently 1 or 2; andring B optionally further has substituent(s), or a salt thereof (seeWO2007/094513).

On the other hand, as heterocyclic compounds, the following compoundshave been reported.

(13) In WO2007/111227, for example, a compound having the followingformula is reported as a CCR4 inhibitor.

(14) In WO2006/101780, for example, a compound having the followingformula is reported as a kinesin inhibitor.

(15) In WO2005/047251, for example, a compound having the followingformula is reported as a melanocortin receptor agonist.

(16) In WO2005/019206, for example, a compound having the followingformula is reported as a kinesin inhibitor.

(17) In WO2005/018547, for example, a compound having the followingformula is reported as a kinesin inhibitor.

(18) In WO2004/037171, for example, a compound having the followingformula is reported as a kinesin inhibitor.

(19) In WO2003/079973, for example, a compound having the followingformula is reported as a kinesin inhibitor.

(20) In WO2003/037274, for example, a compound having the followingformula is reported as a Na⁺ channel inhibitor.

(21) In WO97/09308, for example, a compound having the following formulais reported as a NPY receptor antagonist.

(22) In WO2003/000677, for example, a compound having the followingformula is reported as an ORL-1 receptor ligand.

However, these reports do not describe a renin inhibitory activity.

CITATION LIST Patent Literature

-   patent document 1: WO2009/14217-   patent document 2: WO2009/05002-   patent document 3: WO2009/001915-   patent document 4: WO2008/153182-   patent document 5: WO2008/153135-   patent document 6: WO2008/139941-   patent document 7: WO2008/136457-   patent document 8: WO2009/051112-   patent document 9: WO2008/093737-   patent document 10: WO2007/077005-   patent document 11: WO2007/006534-   patent document 12: WO2007/094513-   patent document 13: WO2007/111227-   patent document 14: WO2006/101780-   patent document 15: WO2005/047251-   patent document 16: WO2005/019206-   patent document 17: WO2005/018547-   patent document 18: WO2004/037171-   patent document 19: WO2003/079973-   patent document 20: WO2003/037274-   patent document 21: WO97/09308-   patent document 22: WO2003/000677

Non Patent Literature

-   non-patent document 1: Chem. Biol., 2000, vol. 7, page 493-504-   non-patent document 2: Hypertension, 2003, vol. 42, page 1137-1143-   non-patent document 3: J. Hypertens., 2005, vol. 23, page 417-426-   non-patent document 4: Journal of Medicinal Chemistry, 1995, vol.    38, page 1406-1410

SUMMARY OF THE INVENTION

There is a demand on the development of a compound having a superiorrenin inhibitory activity, which is useful as a medicament (e.g., agentfor the prophylaxis or treatment of hypertension, various organ damagesattributable to hypertension, and the like) and a novel renin inhibitor.

The present inventors have conducted various studies, and as a result,first succeeded in the creation of novel compounds represented by thefollowing formulas (I) and (II), and a salt thereof, and found that thecompound and a salt thereof unexpectedly have a superior renininhibitory activity, and are useful as medicaments such as renininhibitor and the like, which resulted in the completion of the presentinvention.

The present invention relates to

[1] a compound represented by the formula (I):

whereinR¹ is a hydrogen atom, an alkyl group optionally having substituent(s),an alkenyl group optionally having substituent(s) or a cycloalkyl groupoptionally having substituent(s);R² is a halogen atom, a hydroxy group, a cyano (nitrile) group, an aminogroup optionally having substituent(s), a mercapto group optionallyhaving a substituent (the mercapto group is optionally oxidized), analkyl group optionally having substituent(s) other than a substitutedamino group, an alkoxy group optionally having substituent(s), a 3- to10-membered cyclic hydrocarbon group optionally having substituent(s), a3- to 10-membered heterocyclic group optionally having substituent(s) oran acyl group (wherein when the acyl group is —CONR′R″, then R′ and R″are both hydrogen atoms or form, together with the nitrogen atom bondedthereto, a nitrogen-containing heterocycle optionally havingsubstituent(s));

X is absent, or a hydrogen atom, an alkyl group optionally substitutedby group(s) other than a heterospiro ring optionally havingsubstituent(s) or a cycloalkyl group optionally having substituent(s);and

ring A is a heterocycle optionally having substituent(s), which is otherthan

wherein ring C is a heterocycle optionally having substituent(s), ring Dis a benzene ring optionally having substituent(s), R′″ is a substitutedalkyl group or a substituted alkoxy group, R″″ is a substituent, and Xis as defined above),or a salt thereof;[2] a compound represented by the formula (II):

whereinR¹ is a hydrogen atom, an alkyl group optionally having substituent(s),an alkenyl group optionally having substituent(s) or a cycloalkyl groupoptionally having substituent(s);R³ is an alkyl group optionally substituted by group(s) other than aheterospiro ring optionally having substituent(s), an alkenyl groupoptionally having substituent(s), a cycloalkyl group optionally havingsubstituent(s), an alkylthio group optionally having substituent(s), analkylsulfinyl group optionally having substituent(s), an alkylsulfonylgroup optionally having substituent(s), an alkoxy group optionallyhaving substituent(s), an aryl group optionally having substituent(s) ora heteroaryl group optionally having substituent(s);X¹ is a C₁₋₆ alkylene group optionally substituted by group(s) otherthan a heterospiro ring optionally having substituent(s);ring A¹ is a fused heterocycle optionally having substituent(s);ring B is a 5- to 7-membered nitrogen-containing heterocycle optionallyhaving substituent(s); andn is 0, 1 or 2,or a salt thereof;[3] a compound represented by the formula (II):

whereinR¹ is a hydrogen atom, an alkyl group optionally having substituent(s),an alkenyl group optionally having substituent(s) or a cycloalkyl groupoptionally having substituent(s);R³ is an alkyl group optionally substituted by group(s) other than aheterospiro ring optionally having substituent(s), an alkenyl groupoptionally having substituent(s), a cycloalkyl group optionally havingsubstituent(s), an alkylthio group optionally having substituent(s), analkylsulfinyl group optionally having substituent(s), an alkylsulfonylgroup optionally having substituent(s), an alkoxy group optionallyhaving substituent(s), an aryl group optionally having substituent(s) ora heteroaryl group optionally having substituent(s);X¹ is a C₁₋₆ alkylene group optionally substituted by group(s) otherthan a heterospiro ring optionally having substituent(s);ring A¹ is a fused heterocycle optionally having substituent(s);ring B is a 5- to 7-membered nitrogen-containing heterocycle optionallyhaving substituent(s); andn is 0, 1 or 2, provided that ring A¹ is other than

wherein ring C is a heterocycle optionally having substituent(s), ring Dis a benzene ring optionally having substituent(s), R′″ is a substitutedalkyl group or a substituted alkoxy group, R″″ is a substituent, andother symbols are as defined above,or a salt thereof;[4] a compound represented by the formula (II):

whereinR¹ is a hydrogen atom, an alkyl group optionally having substituent(s),an alkenyl group optionally having substituent(s) or a cycloalkyl groupoptionally having substituent(s);R³ is an alkyl group optionally substituted by group(s) other than aheterospiro ring optionally having substituent(s), an alkenyl groupoptionally having substituent(s), a cycloalkyl group optionally havingsubstituent(s), an alkylthio group optionally having substituent(s), analkylsulfinyl group optionally having substituent(s), an alkylsulfonylgroup optionally having substituent(s), an alkoxy group optionallyhaving substituent(s), an aryl group optionally having substituent(s) ora heteroaryl group optionally having substituent(s);X¹ is a C₁₋₆ alkylene group optionally substituted by group(s) otherthan a heterospiro ring optionally having substituent(s);ring A¹ is a fused heterocycle optionally having substituent(s);ring B is a 5- to 7-membered nitrogen-containing heterocycle optionallysubstituted by substituent(s) selected from a halogen atom, a hydroxygroup, a cyano (nitrile) group, an amino group optionally havingsubstituent(s), a mercapto group optionally having a substituent (themercapto group is optionally oxidized), an alkyl group optionally havingsubstituent(s) other than a substituted amino group, an alkoxy groupoptionally having substituent(s), a 3- to 10-membered cyclic hydrocarbongroup optionally having substituent(s), a 3- to 10-membered heterocyclicgroup optionally having substituent(s), and an acyl group (wherein whenthe acyl group is —CONR′R″, then R′ and R″ are both hydrogen atoms orform, together with the nitrogen atom bonded thereto, anitrogen-containing heterocycle optionally having substituent(s)); andn is 0, 1 or 2,or a salt thereof;[5] a compound represented by the formula (II):

whereinR¹ is a hydrogen atom, an alkyl group optionally having substituent(s),an alkenyl group optionally having substituent(s) or a cycloalkyl groupoptionally having substituent(s);R³ is an alkyl group optionally substituted by group(s) other than aheterospiro ring optionally having substituent(s), an alkenyl groupoptionally having substituent(s), a cycloalkyl group optionally havingsubstituent(s), an alkylthio group optionally having substituent(s), analkylsulfinyl group optionally having substituent(s), an alkylsulfonylgroup optionally having substituent(s), an alkoxy group optionallyhaving substituent(s), an aryl group optionally having substituent(s) ora heteroaryl group optionally having substituent(s);X¹ is a C₁₋₆ alkylene group optionally substituted by group(s) otherthan a heterospiro ring optionally having substituent(s);ring A¹ is a fused heterocycle optionally having substituent(s);ring B is a 5- to 7-membered nitrogen-containing heterocycle optionallysubstituted by substituent(s) selected from a halogen atom, a hydroxygroup, a cyano (nitrile) group, an amino group optionally havingsubstituent(s), a mercapto group optionally having a substituent (themercapto group is optionally oxidized), an alkyl group optionally havingsubstituent(s) other than a substituted amino group, an alkoxy groupoptionally having substituent(s), a 3- to 10-membered cyclic hydrocarbongroup optionally having substituent(s), a 3- to 10-membered heterocyclicgroup optionally having substituent(s), and an acyl group (wherein whenthe acyl group is —CONR′R″, then R′ and R″ are both hydrogen atoms orform, together with the nitrogen atom bonded thereto, anitrogen-containing heterocycle optionally having substituent(s)); andn is 0, 1 or 2, provided ring A¹ is other than

wherein ring C is a heterocycle optionally having substituent(s), ring Dis a benzene ring optionally having substituent(s), R′″ is a substitutedalkyl group or a substituted alkoxy group, R″″ is a substituent, andother symbols are as defined above,or a salt thereof;[6] the compound of any of the above-mentioned [1] to [5], wherein ringA and ring A¹ are each a ring represented by the formula

whereinR^(a) and R^(b) are each independently a hydrogen atom, a halogen atom,an alkyl group optionally having substituent(s), an alkoxy groupoptionally having substituent(s) or an acyl group;R^(c) is a hydrogen atom, a halogen atom, ═O, ═S, an alkyl groupoptionally having substituent(s), an alkoxy group optionally havingsubstituent(s) or an acyl group;Y¹ and Y² are each independently CH or N; andZ is CH₂, NH, O or S;[7] the compound of any of the above-mentioned [1] to [5], wherein ringA and ring A¹ are each a ring represented by the formula

whereinR^(a) and R^(b) are each a hydrogen atom;R^(c) is a hydrogen atom, a halogen atom, ═O, ═S, an alkyl groupoptionally having substituent(s), an alkoxy group optionally havingsubstituent(s) or an acyl group;Y¹ and Y² are each independently CH or N; andZ is CH₂, NH, O or S;[8] the compound of any of the above-mentioned [1] to [5], wherein ringA or ring A¹ is a ring represented by the formula

wherein Y¹, Y², R^(a) and R^(b) are as defined in the above-mentioned[7];[9] the compound of any of the above-mentioned [1] to [5], wherein ringA or ring A¹ is a ring represented by the formula

[10] the compound of any of the above-mentioned [2] to [5], wherein ringB is a ring represented by the formula

whereinR⁴ is a hydrogen atom, a halogen atom, a hydroxy group, a cyano(nitrile) group, an amino group optionally having substituent(s), amercapto group optionally having a substituent (the mercapto group isoptionally oxidized), an alkyl group optionally having substituent(s)other than a substituted amino group, an alkoxy group optionally havingsubstituent(s), a 3- to 10-membered cyclic hydrocarbon group optionallyhaving substituent(s), a 3- to 10-membered heterocyclic group optionallyhaving substituent(s) or an acyl group (wherein when the acyl group is—CONR′R″, then R′ and R″ are both hydrogen atoms or form, together withthe nitrogen atom bonded thereto, a nitrogen-containing heterocycleoptionally having substituent(s));[11] the compound of any of the above-mentioned [2] to [5], wherein ringB is a ring represented by the formula

wherein R⁴ is(1) a hydrogen atom,(2) a cyano (nitrile) group,(3) a C₁₋₆ alkyl group optionally having 1 to 3 substituents selectedfrom(a) a hydroxy group,(b) a C₁₋₆ alkoxy group,(c) a C₁₋₆ alkyl-carbonyloxy group,(d) an aromatic heterocyclic group optionally having 1 to 3 halogenatoms,(e) a C₃₋₁₀ cycloalkyl group, and(f) a cyclic amino group optionally having an oxo group,(4) a 3- to 10-membered heterocyclic group optionally having 1 to 3substituents selected from a C₁₋₆ alkyl group and an oxo group,(5) a carboxy group,(6) a C₁₋₆ alkoxy-carbonyl group optionally having 1 to 3 substituentsselected from a nonaromatic heterocyclic group optionally having 1 to 3substituents selected from a C₁₋₆ alkyl group and an oxo group or(7) a group represented by the formula: —CO—NR′R″wherein R′ and R″ are each a hydrogen atom, or R′ and R″ form, togetherwith the nitrogen atom bonded thereto, a nitrogen-containing heterocycleoptionally having 1 to 3 substituents selected from halogen atom(s);[12] the compound of any of the above-mentioned [2] to [5], wherein ringB is a ring represented by

wherein R⁴ is(1) a cyano (nitrile) group,(2) a C₁₋₆ alkyl group optionally having 1 to 3 substituents selectedfrom(a) a hydroxy group,(b) a C₁₋₆ alkoxy group,(c) a C₁₋₆ alkyl-carbonyloxy group,(d) an aromatic heterocyclic group optionally having 1 to 3 halogenatoms,(e) a C₃₋₁₀ cycloalkyl group, and(f) a cyclic amino group optionally having an oxo group,(3) a 3- to 10-membered heterocyclic group optionally having 1 to 3substituents selected from a C₁₋₆ alkyl group and an oxo group,(4) a carboxy group,(5) a C₁₋₆ alkoxy-carbonyl group optionally having 1 to 3 substituentsselected from a nonaromatic heterocyclic group optionally having 1 to 3substituents selected from a C₁₋₆ alkyl group and an oxo group or(6) a group represented by the formula: —CO—NR′R″wherein R′ and R″ are each a hydrogen atom, orR′ and R″ form, together with the nitrogen atom bonded thereto, anitrogen-containing heterocycle optionally having 1 to 3 substituentsselected from halogen atom(s);[13] the compound of any of the above-mentioned [2] to [5], wherein ringB is a ring represented by

wherein R⁴ is —CO—NR′R″ wherein R′ and R″ are each a hydrogen atom, orR′ and R″ form, together with the nitrogen atom bonded thereto, anitrogen-containing heterocycle optionally having 1 to 3 substituentsselected from halogen atom(s);[14] the compound of any of the above-mentioned [1] to [5], wherein R¹is a C₁₋₆ alkyl group optionally having substituent(s);[15] the compound of the above-mentioned [1], wherein R² is an acylgroup (wherein when the acyl group is —CONR′R″, then R′ and R″ are bothhydrogen atoms or form, together with the nitrogen atom bonded thereto,a nitrogen-containing heterocycle optionally having substituent(s));[16] the compound of the above-mentioned [1], wherein X is a C₁₋₆ alkylgroup optionally substituted by a C₁₋₆ alkoxy group;[17] the compound of any of the above-mentioned [2] to [5], wherein X¹is a C₁₋₆ alkylene group optionally substituted by group(s) other than aheterospiro ring optionally having substituent(s) and an oxo group;[18] the compound of any of the above-mentioned [2] to [5], wherein X¹is a C₁₋₆ alkylene group;[19] the compound of any of the above-mentioned [2] to [5], wherein R³is a C₁₋₆ alkoxy group optionally having substituent(s);[20] the compound of the above-mentioned [1], wherein R¹ is a C₁₋₆ alkylgroup optionally having substituent(s), R² is an acyl group (whereinwhen the acyl group is —CONR′R″, then R′ and R″ are both hydrogen atomsor form, together with the nitrogen atom bonded thereto, anitrogen-containing heterocycle optionally having substituent(s)),

ring A is a ring represented by the formula

wherein Y¹, Y², R^(a) and R^(b) are as defined in the above-mentioned[7], and

X is a C₁₋₆ alkyl group optionally substituted by a C₁₋₆ alkoxy group;

[21] the compound of any of the above-mentioned [2] to [5], wherein R¹is a C₁₋₆ alkyl group optionally having substituent(s),

R³ is a C₁₋₆ alkoxy group optionally having substituent(s), ring A¹ is aring represented by the formula

wherein Y¹, Y², R^(a) and R^(b) are as defined in the above-mentioned[7],X¹ is a C₁₋₆ alkylene group, and

ring B is a ring represented by the formula

wherein R⁴ is —CO—NR′R″ wherein R′ and R″ are each a hydrogen atom, orR′ and R″ form, together with the nitrogen atom bonded thereto, anitrogen-containing heterocycle optionally having 1 to 3 substituentsselected from halogen atom(s);[22]N-[(3S,5R)-5-carbamoylpiperidin-3-yl]-1-(4-methoxybutyl)-N-(2-methylpropyl)-1H-benzimidazole-2-carboxamideor a salt thereof;[23]N-{(3S,5R)-5-[1-hydroxyethyl]piperidin-5-yl}-1-(4-methoxybutyl)-N-(2-methylpropyl)-1H-benzimidazole-2-carboxamideor a salt thereof;[24]1-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamideor a salt thereof;[25]1-(4-hydroxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamideor a salt thereof;[26]1-(2-fluorophenyl)-5-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-1,2,3-triazole-4-carboxamideor a salt thereof;[27]1-(4-methoxybutyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-N-propyl-1H-benzimidazole-2-carboxamideor a salt thereof;[28] a prodrug of the compound of any of the above-mentioned [1] to [5];[29] a medicament comprising the compound of any of the above-mentioned[1] to [5], or a prodrug thereof as an active ingredient;[30] the medicament of the above-mentioned [29], which is a renininhibitor;[31] the medicament of the above-mentioned [29], which is a prophylacticor therapeutic agent of a circulatory disease;[32] the medicament of the above-mentioned [29], which is a prophylacticor therapeutic agent of hypertension and/or various organ damagesattributable to hypertension;[33] a method for the prophylaxis or treatment of a circulatory diseasein a mammal comprising administering the compound of any of theabove-mentioned [1] to [5] or a prodrug thereof to the mammal;[34] a method for the prophylaxis or treatment of hypertension and/orvarious organ damages attributable to hypertension in a mammalcomprising administering the compound of any of the above-mentioned [1]to [5] or a prodrug thereof to the mammal;[35] use of the compound of any of the above-mentioned [1] to[5] or a prodrug thereof for the production of a prophylactic ortherapeutic agent for a circulatory disease;[36] use of the compound of any of the above-mentioned [1] to[5] or a prodrug thereof for the production of a prophylactic ortherapeutic agent for hypertension and/or various organ damagesattributable to hypertension, and the like.

Compound (I) has a superior renin inhibitory activity, and thus it isuseful as an agent for the prophylaxis or treatment of hypertension,various organ damages attributable to hypertension, and the like.

DETAILED DESCRIPTION OF THE INVENTION

Examples of the “halogen atom” in the present specification includefluorine, chlorine, bromine and iodine.

Examples of the “C₁₋₄ alkylenedioxy group” in the present specificationinclude methylenedioxy, ethylenedioxy, trimethylenedioxy and the like.

Examples of the “alkyl group” in the present specification includemethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl,isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl,2-ethylbutyl and the like. Among these, a C₁₋₆ alkyl group ispreferable.

Examples of the “alkenyl group” in the present specification includeethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl,2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl,5-hexenyl and the like. Among these, a C₂₋₆ alkenyl group is preferable.

Examples of the “alkynyl group” in the present specification includeethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl,1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl,3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 1-octynyl and the like.Among these, a C₂₋₆ alkynyl group is preferable.

Examples of the “cycloalkyl group” in the present specification includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, -bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl,bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.1]nonyl,bicyclo[4.2.1]nonyl, bicyclo[4.3.1]decyl, adamantyl and the like. Amongthese, a C₃₋₁₀ cycloalkyl group is preferable.

Examples of the “alkylthio group” in the present specification includemethylthio, ethylthio, propylthio, isopropylthio, butylthio,isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio,neopentylthio, 1-ethylpropylthio, hexylthio, isohexylthio,1,1-dimethylbutylthio, 2,2-dimethylbutylthio, 3,3-dimethylbutylthio,2-ethylbutylthio and the like. Among these, a C₁₋₆ alkylthio group ispreferable.

Examples of the “alkylsulfinyl group” in the present specificationinclude methylsulfinyl, ethylsulfinyl, propylsulfinyl,isopropylsulfinyl, butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl,tert-butylsulfinyl, pentylsulfinyl, isopentylsulfinyl,neopentylsulfinyl, 1-ethylpropylsulfinyl, hexylsulfinyl,isohexylsulfinyl, 1,1-dimethylbutylsulfinyl, 2,2-dimethylbutylsulfinyl,3,3-dimethylbutylsulfinyl, 2-ethylbutylsulfinyl and the like. Amongthese, a C₁₋₆ alkylsulfinyl group is preferable.

Examples of the “alkylsulfonyl group” in the present specificationinclude methylsulfonyl, ethylsulfonyl, propylsulfonyl,isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl,tert-butylsulfonyl, pentylsulfonyl, isopentylsulfonyl,neopentylsulfonyl, 1-ethylpropylsulfonyl, hexylsulfonyl,isohexylsulfonyl, 1,1-dimethylbutylsulfonyl, 2,2-dimethylbutylsulfonyl,3,3-dimethylbutylsulfonyl, 2-ethylbutylsulfonyl and the like. Amongthese, a C₁₋₆ alkylsulfonyl group is preferable.

Examples of the “alkoxy group” in the present specification includemethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, 1-ethylpropyloxy,hexyloxy, isohexyloxy, 1,1-dimethylbutyloxy, 2,2-dimethylbutyloxy,3,3-dimethylbutyloxy, 2-ethylbutyloxy and the like. Among these, a C₁₋₆alkoxy group is preferable.

Examples of the “C₁₋₆ alkoxy-carbonyl group” in the presentspecification include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,tert-butoxycarbonyl and the like.

Examples of the “C₁₋₆ alkyl-carbonyl group” in the present specificationinclude acetyl, propanoyl, butanoyl, isobutanoyl, pentanoyl,isopentanoyl, hexanoyl and the like.

The “optionally halogenated” in the present specification means beingoptionally substituted by 1 to 5, preferably 1 to 3, halogen atoms.

Examples of the “C₁₋₆ alkylene group” in the present specificationinclude methylene, ethylene, trimethylen, tetramethylene,pentamethylene, hexamethylene, —CH(CH₃)—, —C(CH₃)₂—, —CH(CH₂CH₃)—,—C(CH₂CH₃)₂—, —CH(CH₃)—CH₂—, —CH₂—CH(CH₃)—, —C(CH₃)₂—CH₂—,—CH₂—C(CH₃)₂—, —CH(CH₃)—(CH₂)₂—, —CH₂—CH(CH₃)—CH₂—, —(CH₂)₂—CH(CH₃)—,—C(CH₃)₂—(CH₂)₂—, —CH₂—C(CH₃)₂—CH₂—, —(CH₂)₂—C(CH₃)₂— and the like.

Examples of the “hydrocarbon group” of the “hydrocarbon group optionallyhaving substituent(s)” in the present specification include alkyl group,alkenyl group, alkynyl group, alkylidene group, cycloalkyl group,cycloalkenyl group, cycloalkadienyl group, aryl group, aralkyl group,arylalkenyl group, cycloalkylalkyl group and the like. Preferably, C₁₋₁₀alkyl group, C₂₋₁₀ alkenyl group, C₂₋₁₀ alkynyl group, C₁₋₃ alkylidenegroup, C₃₋₁₀ cycloalkyl group, C₃₋₁₀ cycloalkenyl group, C₄₋₁₀cycloalkadienyl group, C₆₋₁₄ aryl group, C₇₋₁₆ aralkyl group, C₈₋₁₃arylalkenyl group, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl group and the like. Theabove-mentioned C₃₋₁₀ cycloalkyl group, C₃₋₁₀ cycloalkenyl group andC₄₋₁₀ cycloalkadienyl group may be each condensed with a benzene ring.

Examples of the “C₁₋₁₀ alkyl group” in the present specification includemethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl,isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl,2-ethylbutyl, heptyl, octyl, nonyl, decyl and the like. Among these, aC₁₋₆ alkyl group is preferable.

Examples of the “C₂₋₁₀ alkenyl group” in the present specificationinclude ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl,2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl,5-hexenyl, 1-heptenyl, 1-octenyl and the like. Among these, a C₂₋₆alkenyl group is preferable.

Examples of the “C₂₋₁₀ alkynyl group” in the present specificationinclude ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl,2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 1-octynyl andthe like. Among these, a C₂₋₆ alkynyl group is preferable.

Examples of the “C₁₋₃ alkylidene group” in the present specificationinclude methylidene, ethylidene, propylidene, isopropylidene and thelike.

Examples of the “C₃₋₁₀ cycloalkyl group” in the present specificationinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl,bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.1]nonyl,bicyclo[4.2.1]nonyl, bicyclo[4.3.1]decyl, adamantyl and the like. Amongthese, a C₃₋₆ cycloalkyl group is preferable. The above-mentioned C₃₋₁₀cycloalkyl may be condensed with a benzene ring, and examples of thefused group include indanyl, tetrahydronaphthyl, fluorenyl and the like.

Examples of the “C₃₋₁₀ cycloalkenyl group” in the present specificationinclude 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl,3-cyclohexen-1-yl and the like. The above-mentioned C₃₋₁₀ cycloalkenylmay be condensed with a benzene ring, and examples of the fused groupinclude indenyl and the like.

Examples of the “C₄₋₁₀ cycloalkadienyl group” in the presentspecification include 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl,2,5-cyclohexadien-1-yl and the like. The above-mentioned C₁₋₁₀cycloalkadienyl may be condensed with a benzene ring.

Examples of the “C₆₋₁₄ aryl group” in the present specification includephenyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-anthryl and the like.Among these, a C₆₋₁₀ aryl group is preferable, and phenyl is morepreferable. The above-mentioned C₆₋₁₄ aryl may be condensed with C₃₋₁₀cycloalkane (examples of the C₃₋₁₀ cycloalkane include a ringcorresponding to the above-mentioned C₃₋₁₀ cycloalkyl group), andexamples of the fused group include tetrahydronaphthyl, indanyl and thelike.

Examples of the “C₇₋₁₆ aralkyl group” in the present specificationinclude benzyl, phenethyl, naphthylmethyl, biphenylylmethyl and thelike.

Examples of the “C₈₋₁₃ arylalkenyl group” in the present specificationinclude styryl and the like.

Examples of the “C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl group” in the presentspecification include cyclopropylmethyl, cyclohexylmethyl and the like.

The “hydrocarbon group” of the “hydrocarbon group optionally havingsubstituent(s)” optionally has substituent(s) (e.g., 1 to 5, preferably1 to 3 substituents) at substitutable position(s). When the number ofthe substituents is two or more, respective substituents may be the sameor different.

Examples of the “substituent” of the “hydrocarbon group optionallyhaving substituent(s)” include the following substituents (hereinafterto be referred to as substituent group A).

(1) a halogen atom;

(2) a nitro group;

(3) a cyano (nitrile) group;

(4) a hydroxy group;

(5) an alkoxy group optionally having substituent(s);

(6) an amino group optionally having substituent(s);

(7) ═O (oxo group);

(8) ═S (thioxo group);

(9) a mercapto group optionally having a substituent (the mercapto groupis optionally oxidized);

(10) a C₁₋₄ alkylenedioxy group;

(11) an alkyl group optionally having substituent(s);

(12) a C₇₋₁₆ aralkyl group;

(13) an acyl group;

(14) a 3- to 10-membered cyclic hydrocarbon group optionally havingsubstituent(s);

(15) a 3- to 10-membered heterocyclic group optionally havingsubstituent(s) and the like.

Examples of the “3- to 10-membered cyclic hydrocarbon group” of the “3-to 10-membered cyclic hydrocarbon group optionally havingsubstituent(s)” for substituent group A include C₃₋₁₀ cycloalkyl group,C₃₋₁₀ cycloalkenyl group, C₄₋₁₀ cycloalkadienyl group, C₆₋₁₀ aryl groupand the like. Examples of the C₃₋₁₀ cycloalkyl group, C₃₋₁₀ cycloalkenylgroup, C₄₋₁₀ cycloalkadienyl group and C₆₋₁₀ aryl group include thosesimilar to the C₃₋₁₀ cycloalkyl group, C₃₋₁₀ cycloalkenyl group, C₄₋₁₀cycloalkadienyl group and C₆₋₁₀ aryl group exemplified as the“hydrocarbon group” of the “hydrocarbon group optionally havingsubstituent(s)”.

Examples of the “3- to 10-membered heterocyclic group” of the “3- to10-membered heterocyclic group optionally having substituent(s)” forsubstituent group A include a 3- to 10-membered ring from the“heterocyclic group” of the “heterocyclic group optionally havingsubstituent(s)” to be mentioned later.

Examples of the “substituent” of the “C₁₋₆ alkyl group optionally havingsubstituent(s)” and “C₁₋₆ alkoxy group optionally havingsubstituent(s)”, “3- to 10-membered cyclic hydrocarbon group optionallyhaving substituent(s)” and “3- to 10-membered heterocyclic groupoptionally having substituent(s)” for substituent group A include 1 to5, preferably 1 to 3 selected from the following substituents(hereinafter to be referred to as substituent group B). When the numberof the substituents is two or more, the respective substituents may bethe same or different.

(1) a halogen atom;

(2) a nitro group;

(3) a cyano (nitrile) group;

(4) a hydroxy group;

(5) a C₁₋₆ alkoxy group optionally having 1 to 3 halogen atoms;

(6) an amino group;

(7) a mono- or di-C₁₋₆ alkylamino group;

(8) a C₇₋₁₆ aralkylamino group;

(9) a C₁₋₆ alkoxy-carbonylamino group;

(10) a C₁₋₆ alkyl-carbonylamino group;

(11) a C₁₋₆ alkyl-carbonyloxy group;

(12) a C₁₋₆ alkyl-carbonyl group;

(13) a carboxy group;

(14) a C₁₋₆ alkoxy-carbonyl group;

(15) a carbamoyl group;

(16) a mono- or di-C₁₋₆ alkylcarbamoyl group;

(17) ═O (oxo group);

(18) ═S (thioxo group);

(19) a mercapto group;

(20) a C₁₋₆ alkylthio group;

(21) a C₁₋₆ alkylsulfinyl group;

(22) a C₁₋₆ alkylsulfonyl group;

(23) a C₁₋₄ alkylenedioxy group;

(24) a C₁₋₆ alkyl group optionally having 1 to 3 substituents selectedfrom

(a) a halogen atom,

(b) a hydroxy group,

(c) a C₁₋₆ alkoxy group,

(d) a C₆₋₁₄ aryl group,

(e) an amino group,

(f) a mono- or di-C₁₋₆ alkylamino group,

(g) a C₇₋₁₆ aralkylamino group, and

(h) a C₁₋₆ alkoxy-carbonylamino group;

(25) an aryl group optionally having 1 to 3 halogen atoms;

(26) an aromatic heterocyclic group (e.g., pyridyl, pyrazolyl,triazolyl) optionally having 1 to 3 halogen atoms;

(27) a nonaromatic heterocyclic group (e.g., dioxolyl) optionally having1 to 3 substituents selected from a C₁₋₆ alkyl group and an oxo group;

(28) a C₇₋₁₆ aralkyl group;

(29) a C₃₋₁₀ cycloalkyl group;

(30) a cyclic amino group (e.g., pyrrolidinyl, piperidino, morpholino,thiomorpholino, piperazinyl, imidazolidin-1-yl, pyrazolidin-1-yl etc.)optionally having an oxo group and the like.

Examples of the “substituent” of the “amino group optionally havingsubstituent(s)” for substituent group A include 1 or 2 selected fromsubstituent group B. When the number of the substituents is two, therespective substituents may be the same or different.

Examples of the “substituent” of the “mercapto group optionally having asubstituent” for substituent group A include substituent group B. Themercapto group may be oxidized by 1 or 2 oxygens.

Examples of the “heterocyclic group” of the “heterocyclic groupoptionally having substituent(s)” in the present specification includean aromatic heterocyclic group and a nonaromatic heterocyclic group.

Examples of the “aromatic heterocyclic group” include a 4- to10-membered (preferably 5- or 6-membered) monocyclic aromaticheterocyclic group containing, as a ring-constituting atom besidescarbon atoms, 1 to 4 heteroatoms selected from an oxygen atom, a sulfuratom and a nitrogen atom, and a fused aromatic heterocyclic group.Examples of the fused aromatic heterocyclic group include a groupderived from a fused ring wherein a ring corresponding to such 4- to10-membered monocyclic aromatic heterocyclic group, and 1 or 2 ringsselected from a 5- or 6-membered aromatic heterocycle containing 1 or 2nitrogen atoms, a 5-membered aromatic heterocycle containing one sulfuratom and a benzene ring are condensed, and the like.

Examples of the “aromatic heterocyclic group” include 4- to 7-membered(preferably 5- or 6-membered) monocyclic aromatic heterocyclic groupssuch as furyl (e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl,3-thienyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl(e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (e.g.,3-pyridazinyl, 4-pyridazinyl), pyrazinyl (e.g., 2-pyrazinyl), pyrrolyl(e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (e.g.,1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), pyrazolyl(e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), thiazolyl (e.g.,2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolyl (e.g.,3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), oxazolyl (e.g.,2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (e.g., 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 1,2,4-oxadiazol-5-yl,1,3,4-oxadiazol-2-yl), thiadiazolyl (e.g., 1,2,4-thiadiazol-5-yl,1,3,4-thiadiazol-2-yl), triazolyl (e.g., 1,2,4-triazol-1-yl,1,2,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl,1,2,3-triazol-4-yl), tetrazolyl (e.g., tetrazol-1-yl, tetrazol-5-yl),triazinyl (e.g., 1,3,5-triazin-2-yl, 1,3,5-triazin-4-yl,1,2,3-triazin-4-yl, 1,2,4-triazin-3-yl) and the like;

fused aromatic heterocyclic groups such as quinolyl (e.g., 2-quinolyl,3-quinolyl, 4-quinolyl, 6-quinolyl), isoquinolyl (e.g., 3-isoquinolyl),quinazolyl (e.g., 2-quinazolyl, 4-quinazolyl), quinoxalyl (e.g.,2-quinoxalyl, 6-quinoxalyl), benzofuranyl (e.g., 2-benzofuranyl,3-benzofuranyl), benzothienyl (e.g., 2-benzothienyl, 3-benzothienyl),benzoxazolyl (e.g., 2-benzoxazolyl), benzisoxazolyl (e.g.,7-benzisoxazolyl), benzothiazolyl (e.g., 2-benzothiazolyl),benzimidazolyl (e.g., benzimidazol-1-yl, benzimidazol-2-yl,benzimidazol-5-yl), benzotriazolyl (e.g., 1H-1,2,3-benzotriazol-5-yl),indolyl (e.g., indol-1-yl, indol-2-yl, indol-3-yl, indol-5-yl),indazolyl (e.g., 1H-indazol-3-yl), pyrrolopyrazinyl (e.g.,1H-pyrrolo[2,3-b]pyrazin-2-yl, 1H-pyrrolo[2,3-b]pyrazin-6-yl),imidazopyridyl (e.g., 1H-imidazo[4,5-b]pyridin-2-yl,1H-imidazo[4,5-c]pyridin-2-yl, 2H-imidazo[1,2-a]pyridin-3-yl),imidazopyrazinyl (e.g., 1H-imidazo[4,5-b]pyrazin-2-yl), pyrazolopyridyl(e.g., 1H-pyrazolo[4,3-c]pyridin-3-yl), pyrazolothienyl (e.g.,2H-pyrazolo[3,4-b]thiophen-2-yl), pyrazolotriazinyl (e.g.,pyrazolo[5,1-c][1,2,4]triazin-3-yl) and the like; and the like.

Examples of the “non-aromatic heterocyclic group” include a 3- to10-membered (preferably 5- or 6-membered) monocyclic non-aromaticheterocyclic group containing, as a ring-constituting atom besidescarbon atoms, 1 to 4 heteroatoms selected from an oxygen atom, a sulfuratom and a nitrogen atom, and a fused non-aromatic heterocyclic group.Examples of the fused non-aromatic heterocyclic group include a groupderived from a fused ring wherein a ring corresponding to such 3- to10-membered monocyclic non-aromatic heterocyclic group, and 1 or 2 ringsselected from a 5- or 6-membered heterocycle containing 1 or 2 nitrogenatoms, a 5-membered heterocycle containing one sulfur atom and a benzenering are condensed, and the like.

Examples of the “non-aromatic heterocyclic group” include 4- to7-membered (preferably 5- or 6-membered) monocyclic non-aromaticheterocyclic groups such as pyrrolidinyl (e.g., 1-pyrrolidinyl,2-pyrrolidinyl), piperidinyl (e.g., piperidino, 2-piperidinyl,3-piperidinyl, 4-piperidinyl), morpholinyl (e.g., morpholino),thiomorpholinyl (e.g., thiomorpholino), piperazinyl (e.g.,1-piperazinyl, 2-piperazinyl, 3-piperazinyl), hexamethyleniminyl (e.g.,hexamethylenimin-1-yl), oxazolidinyl (e.g., oxazolidin-2-yl),thiazolidinyl (e.g., thiazolidin-2-yl), imidazolidinyl (e.g.,imidazolidin-2-yl, imidazolidin-3-yl), oxazolinyl (e.g., oxazolin-2-yl),thiazolinyl (e.g., thiazolin-2-yl), imidazolinyl (e.g., imidazolin-2-yl,imidazolin-3-yl), dioxolyl (e.g., 1,3-dioxol-4-yl), dioxolanyl (e.g.,1,3-dioxolan-4-yl), dihydrooxadiazolyl (e.g.,4,5-dihydro-1,2,4-oxadiazol-3-yl), 2-thioxo-1,3-oxazolidin-5-yl, pyranyl(e.g., 4-pyranyl), tetrahydropyranyl (e.g., 2-tetrahydropyranyl,3-tetrahydropyranyl, 4-tetrahydropyranyl), thiopyranyl (e.g.,4-thiopyranyl), tetrahydrothiopyranyl (e.g., 2-tetrahydrothiopyranyl,3-tetrahydrothiopyranyl, 4-tetrahydrothiopyranyl),1-oxidotetrahydrothiopyranyl (e.g., 1-oxidotetrahydrothiopyran-4-yl),1,1-dioxidotetrahydrothiopyranyl (e.g.,1,1-dioxidotetrahydrothiopyran-4-yl), tetrahydrofuryl (e.g.,tetrahydrofuran-3-yl, tetrahydrofuran-2-yl), pyrazolidinyl (e.g.,pyrazolidin-1-yl, pyrazolidin-3-yl), pyrazolinyl (e.g., pyrazolin-1-yl),tetrahydropyrimidinyl (e.g., tetrahydropyrimidin-1-yl),hexahydropyrimidinyl (e.g., hexahydropyrimidin-1-yl), dihydrotriazolyl(e.g., 2,3-dihydro-1H-1,2,3-triazol-1-yl), tetrahydrotriazolyl (e.g.,2,3,4,5-tetrahydro-1H-1,2,3-triazol-1-yl) and the like; fusednon-aromatic heterocyclic groups such as dihydroindolyl (e.g.,2,3-dihydro-1H-indol-1-yl), dihydroisoindolyl (e.g.,1,3-dihydro-2H-isoindol-2-yl), dihydrobenzofuranyl (e.g.,2,3-dihydrobenzofuran-5-yl), dihydrobenzodioxinyl (e.g.,2,3-dihydro-1,4-benzodioxinyl), dihydrobenzodioxepinyl (e.g.,3,4-dihydro-2H-1,5-benzodioxepinyl), tetrahydrobenzofuranyl (e.g.,4,5,6,7-tetrahydrobenzofuran-3-yl), chromenyl (e.g., 4H-chromen-2-yl,2H-chromen-3-yl), dihydroquinolinyl (e.g., 1,2-dihydroquinolin-4-yl),tetrahydroquinolinyl (e.g., 1,2,3,4-tetrahydroquinolin-4-yl),dihydroisoquinolinyl (e.g., 1,2-dihydroisoquinolin-4-yl),tetrahydroisoquinolinyl (e.g., 1,2,3,4-tetrahydroisoquinolin-4-yl),dihydrophthalazinyl (e.g., 1,4-dihydrophthalazin-4-yl) and the like; andthe like.

The above-mentioned “heterocyclic group” optionally has substituent(s)(e.g., 1 to 5, preferably 1 to 3 substituents) at substitutableposition(s). When the number of the substituents is two or more, therespective substituents may be the same or different.

Examples of the “substituent” of the “heterocyclic group optionallyhaving substituents” include the groups exemplified as theaforementioned substituent group A and the like.

Examples of the “acyl group” in the present specification include groupsrepresented by the formulas: —COR^(A), —CO—OR^(A), —SO₂R^(A), —SOR^(A),—CO—NR′R″, —CS—NR′R″ wherein RA is a hydrogen atom, a hydroxy group, ahydrocarbon group optionally having substituent(s), an amino groupoptionally having substituent(s) or a heterocyclic group optionallyhaving substituent(s). R′ and R″ are each a hydrogen atom, a hydrocarbongroup optionally having substituent(s) or a heterocyclic groupoptionally having substituent(s), or R′ and R″ form, together with thenitrogen atom bonded thereto, a nitrogen-containing heterocycleoptionally having substituent(s), and the like.

Examples of the “hydrocarbon group” of the “hydrocarbon group optionallyhaving substituent(s)” for R^(A), R′ or R″ include those similar to the“hydrocarbon group” of the aforementioned “hydrocarbon group optionallyhaving substituent(s)”.

Examples of the “heterocyclic group” of the “heterocyclic groupoptionally having substituent(s)” for R^(A), R′ or R″ include thosesimilar to the “heterocyclic group” of the aforementioned “heterocyclicgroup optionally having substituent(s)”.

Examples of the “amino group optionally having substituent(s)” for R^(A)include those similar to the “amino group optionally havingsubstituent(s)” of the aforementioned substituent group A.

Examples of the substituent of the “hydrocarbon group optionally havingsubstituent(s)” and “heterocyclic group optionally havingsubstituent(s)” for R^(A), R′ or R″ include 1 to 5, preferably 1 to 3,selected from the aforementioned substituent group A. When the number ofthe substituents is two or more, the respective substituents may be thesame or different.

Examples of the “nitrogen-containing heterocycle” of the“nitrogen-containing heterocycle optionally having substituent(s)”formed by R′ and R″ together with the nitrogen atom bonded theretoinclude a 4- to 7-membered nonaromatic nitrogen-containing heterocyclecontaining, as a ring-constituting atom besides carbon atom, onenitrogen atom, and optionally further containing 1 or 2 hetero atomsselected from an oxygen atom, a sulfur atom and a nitrogen atom. Thenonaromatic nitrogen-containing heterocycle may be condensed with abenzene ring.

Examples of the nitrogen-containing heterocycle include azetidine,pyrrolidine, imidazolidine, pyrazolidine, piperidine, homopiperidine,piperazine, homopiperazine, morpholine, homomorpholine, thiomorpholine,thiohomomorpholine, dihydrobenzoxazine (e.g.,3,4-dihydro-2H-1,4-benzoxazine), 1,2,3,4-tetrahydroquinoline,7-aza-bicyclo[2.2.1]heptane and the like.

The “nitrogen-containing heterocycle” optionally has (preferably 1 to 3,more preferably 1 or 2) substituent(s) at substitutable position(s).Examples of the substituent include substituent group B and the like.When the number of the substituents is two or more, the respectivesubstituents may be the same or different.

Preferable examples of the “acyl” include

(1) a formyl group;

(2) a carboxy group;

(3) a C₁₋₆ alkyl-carbonyl group;

(4) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, tert-butoxycarbonyl) optionally having 1 to 3substituents selected from the substituent group B;

(5) a group represented by the formula: —CO—NR′R″ wherein R′ and R″ areeach a hydrogen atom, a hydrocarbon group optionally having 1 to 3substituents selected from the aforementioned substituent group B or aheterocyclic group optionally having 1 to 3 substituents selected fromthe aforementioned substituent group B, or R′ and R″ optionally form,together with the nitrogen atom bonded thereto, a nitrogen-containingheterocycle optionally having 1 to 3′ substituents selected from theaforementioned substituent group B, and the like.

Examples of the “aryl group” in the present specification include C₆₋₁₄aryl such as phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-anthryl andthe like. Among these, C₆₋₁₀ aryl is preferable and phenyl is morepreferable. The above-mentioned aryl may be condensed with C₃₋₁₀cycloalkane (examples of the C₃₋₁₀ cycloalkane include a ringcorresponding to the above-mentioned C₃₋₁₀ cycloalkyl), and examples ofthe fused group include tetrahydronaphthyl, indanyl and the like.

Examples of the “heteroaryl group” in the present specification includea monocyclic aromatic heterocyclic group and a fused aromaticheterocyclic group from the “heterocyclic group” of the aforementioned“heterocycle optionally having substituent(s)”.

Examples of the “heterocycle” in the present specification includemonocyclic heterocycle and fused heterocycle.

Examples of the “monocyclic heterocycle” include monocyclic aromaticheterocycle and monocyclic non-aromatic heterocycle.

Examples of the “monocyclic aromatic heterocycle” include a 4- to10-membered (preferably 5- or 6-membered) monocyclic aromaticheterocycle containing, as a ring-constituting atom besides carbonatoms, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atomand a nitrogen atom.

Examples of the “monocyclic aromatic heterocycle” include a 4- to7-membered (preferably 5- or 6-membered) monocyclic aromatic heterocyclesuch as furan, thiophene, pyridine, pyrimidine, pyridazine, pyrazine,pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole,oxadiazolyl (e.g., 1,2,4-oxadiazole, 1,3,4-oxadiazole), thiadiazole(e.g., 1,2,4-thiadiazole, 1,3,4-thiadiazole), triazole (e.g.,1,2,4-triazole, 1,2,3-triazole), tetrazole, triazine (e.g.,1,3,5-triazine, 1,2,3-triazine, 1,2,4-triazine) and the like.

Examples of the “monocyclic non-aromatic heterocycle” include a 3- to10-membered (preferably 5- or 6-membered) monocyclic non-aromaticheterocycle containing, as a ring-constituting atom besides carbonatoms, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atomand a nitrogen atom.

Examples of the “monocyclic non-aromatic heterocycle” include a 4- to7-membered (preferably 5- or 6-membered) monocyclic non-aromaticheterocycle such as pyrrolidine, piperidine, morpholine, thiomorpholine,piperazine, hexamethylenimine, oxazolidine, thiazolidine, imidazolidine,oxazoline, thiazoline, imidazoline, dioxole, dioxolane,dihydrooxadiazole (e.g., 4,5-dihydro-1,2,4-oxadiazole),2-thioxo-1,3-oxazolidine, pyran, tetrahydropyran, thiopyran,tetrahydrothiopyran, 1-oxidetetrahydrothiopyran,1,1-dioxidetetrahydrothiopyran, tetrahydrofuran, pyrazolidine,pyrazoline, tetrahydropyrimidine, dihydrotriazole, tetrahydrotriazole(e.g., 2,3,4,5-tetrahydro-1H-1,2,3-triazole) and the like

Examples of the “fused heterocycle” include fused aromatic heterocycleand fused non-aromatic heterocycle.

Examples of the “fused aromatic heterocycle” include a ring wherein a 4-to 7-membered (preferably 5- or 6-membered) monocyclic aromaticheterocycle containing, as a ring-constituting atom besides carbonatoms, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atomand a nitrogen atom, and 1 or 2 rings selected from a 5- or 6-memberedaromatic heterocycle containing 1 or 2 nitrogen atoms, a 5-memberedaromatic heterocycle containing one sulfur atom and a benzene ring arecondensed and the like.

Examples of the “fused aromatic heterocycle” include quinoline,isoquinoline, quinazoline, quinoxaline, benzofuran, benzothiophene,benzoxazole, benzisoxazole, benzothiazole, benzimidazole, benzotriazole,indole, indazole, pyrrolopyrazine (e.g., 1H-pyrrolo[2,3-b]pyrazine),imidazopyridine (e.g., 3H-imidazo[4,5-b]pyridine,1H-imidazo[5,4-b]pyridine, 1H-imidazo[4,5-c]pyridine,imidazo[1,2-a]pyridine), imidazopyrazine (e.g.,1H-imidazo[4,5-b]pyrazine, imidazo[1,2-a]pyrazine), imidazopyrimidine(e.g., imidazo[1,2-a]pyrimidine, imidazo[1,2-c]pyrimidine),imidazopyridazine (e.g., imidazo[1,2-b]pyridazine), pyrazolopyridine(e.g., 1H-pyrazolo[4,3-c]pyridine), thienopyrrole (e.g.,4H-thieno[3,2-b]pyrrole), pyrazolothiophene (e.g.,2H-pyrazolo[3,4-b]thiophene), pyrazolotriazine (e.g.,pyrazolo[5,1-c][1,2,4]triazine), pyrrolopyridine (e.g.,1H-pyrrolo[1,2-b]pyridine), 1,4-dihydropyrrolo[3,2-b]pyrrole,4H-furo[3,2-b]pyrrole, 4H-thieno[3,2-b]pyrrole, 1H-furo[2,3-d]imidazole,1H-thieno[2,3-d]imidazole and the like.

Examples of the “fused non-aromatic heterocycle” include a ring whereina 4- to 7-membered (preferably 5- or 6-membered) monocyclic non-aromaticheterocycle containing, as a ring-constituting atom besides carbonatoms, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atomand a nitrogen atom, and 1 or 2 rings selected from a 5- or 6-memberedaromatic heterocycle containing 1 or 2 nitrogen atoms, a 5-memberedaromatic heterocycle containing one sulfur atom and a benzene ring arecondensed, and the like.

Examples of the “fused non-aromatic heterocycle” include dihydroindole(e.g., 1,2-dihydroindole), tetrahydroindole (e.g.,4,5,6,7-tetrahydro-1H-indole), dihydroisoindole, tetrahydroisoindole(e.g., 4,5,6,7-tetrahydroisoindole), dihydrobenzofuran,dihydrobenzodioxine (e.g., 2,3-dihydro-1,4-benzodioxine),dihydrobenzodioxepine (e.g., 3,4-dihydro-2H-1,5-benzodioxepine),tetrahydrobenzimidazole (e.g., 4,5,6,7-tetrahydro-1H-benzimidazole),tetrahydrobenzofuran (e.g., 4,5,6,7-tetrahydrobenzofuran), chromene(e.g., 4H-chromene, 2H-chromene), dihydroquinoline (e.g.,1,2-dihydroquinoline), tetrahydroquinoline (e.g.,1,2,3,4-tetrahydroquinoline), dihydroisoquinoline (e.g.,1,2-dihydroisoquinoline), tetrahydroisoquinoline (e.g.,1,2,3,4-tetrahydroisoquinoline), dihydrophthalazine (e.g.,1,4-dihydrophthalazine), 1,4-dihydrocyclopenta[b]pyrrole,1,4-dihydrocyclopentaimidazole, 1,4-dihydropyrrolo[2,3-d]imidazole andthe like.

Examples of the “5- to 7-membered nitrogen-containing heterocycle” inthe present specification include pyrrolidine, piperidine andhomopiperidine.

Each symbol in the formulas (I) and (II) is defined in detail in thefollowing.

R¹

In the formulas (I) and (II), R¹ is a hydrogen atom, an alkyl groupoptionally having substituent(s), an alkenyl group optionally havingsubstituent(s) or a cycloalkyl group optionally having substituent(s).

Examples of the substituent of the “alkyl group optionally havingsubstituent(s)”, “alkenyl group optionally having substituent(s)” and“cycloalkyl group optionally having substituent(s)” for R¹ include 1 to5, preferably 1 to 3 selected from the aforementioned substituent groupA. When the number of the substituents is two or more, the respectivesubstituents may be the same or different.

R¹ is preferably a hydrogen atom or a C₁₋₆ alkyl group optionally havingsubstituent(s), more preferably a C₁₋₆ alkyl group (e.g., methyl group,ethyl group, propyl group, isopropyl group, isobutyl group etc.)optionally having 1 to 3 substituents selected from halogen atom(s), acyano group, a hydroxy group, a C₃₋₁₀ cycloalkyl (e.g., cyclopropyl) andthe like, and still more preferably, a C₁₋₆ alkyl group (particularly,isobutyl).

R²

In the formula (I), R² is a halogen atom, a hydroxy group, a cyano(nitrile) group, an amino group optionally having substituent(s), amercapto group optionally having a substituent (the mercapto group isoptionally oxidized), an alkyl group optionally having substituent(s)other than a substituted amino group, an alkoxy group optionally havingsubstituent(s), a 3- to 10-membered cyclic hydrocarbon group optionallyhaving substituent(s), a 3- to 10-membered heterocyclic group optionallyhaving substituent(s), or an acyl group (wherein when the acyl group is—CONR′R″, then R′ and R″ are both hydrogen atoms or form, together withthe nitrogen atom bonded thereto, a nitrogen-containing heterocycleoptionally having substituent(s)).

The “amino group” of the “amino group optionally having substituent(s)”for R² optionally has 1 or 2 substituents at substitutable position(s).When the number of the substituents is two, the respective substituentsmay be the same or different. Examples of the substituent include theaforementioned substituent group B.

The “mercapto group” of the “mercapto group optionally having asubstituent” for R² optionally has a substituent and optionally oxidizedby 1 or 2 oxygens. Examples of the substituent include theaforementioned substituent group B.

The “alkyl group” of the “alkyl group optionally having substituent(s)other than a substituted amino group” for R² optionally has (forexample, 1 to 5, preferably 1 to 3) substituent(s) other than asubstituted amino group at substitutable position(s). When the number ofthe substituents is two or more, the respective substituents may be thesame or different. Examples of the substituent include substituent groupB (except mono- or di-C₁₋₆ alkylamino group, C₇₋₁₆ aralkylamino group,C₁₋₆ alkoxy-carbonylamino group and C₁₋₆ alkyl-carbonylamino group).Examples of the “substituent” of the “substituted amino group” includeunsubstituted or substituted alkyl, unsubstituted or substitutedalkenyl, unsubstituted or substituted alkynyl, unsubstituted orsubstituted aryl, unsubstituted or substituted heterocyclyl orunsubstituted or substituted cycloalkyl or acyl (e.g., C₁₋₆ cycloalkylgroup or C₁₋₆ alkyl group substituted by heterocycle) and the like.

The “alkoxy group” of the “alkoxy group optionally havingsubstituent(s)” for R² optionally has (for example, 1 to 5, preferably 1to 3) substituent(s). When the number of the substituents is two ormore, the respective substituents may be the same or different. Examplesof the substituent include the aforementioned substituent group B.

The “cyclic hydrocarbon group” of the “3- to 10-membered cyclichydrocarbon group optionally having substituent(s)” and the“heterocyclic group” of the “3- to 10-membered heterocyclic groupoptionally having substituent(s)” for R² optionally has (for example, 1to 5, preferably 1 to 3) substituent(s). When the number of thesubstituents is two or more, the respective substituents may be the sameor different. Examples of the substituent include the aforementionedsubstituent group B.

Examples of the “cyclic hydrocarbon group” of the “3- to 10-memberedcyclic hydrocarbon group optionally having substituent(s)” for R²include those similar to the “3- to 10-membered cyclic hydrocarbongroup” of the “3- to 10-membered cyclic hydrocarbon group optionallyhaving substituent(s)” of the aforementioned substituent group A.

Examples of the “heterocyclic group” of the “3- to 10-memberedheterocyclic group optionally having substituent(s)” for R² includethose similar to the “heterocyclic group” of the “3- to 10-memberedheterocyclic group optionally having substituent(s)” of theaforementioned substituent group A.

When the “acyl group” for R² is —CO—NR′R″, R′ and R″ are both hydrogenatoms or form, together with the nitrogen atom bonded thereto, anitrogen-containing heterocycle optionally having substituent(s).Examples of the nitrogen-containing heterocycle include those mentionedabove, and morpholine is particularly preferable.

Examples of the substituent of the “nitrogen-containing heterocycleoptionally having substituent(s)” formed by R′ and R″ together with thenitrogen atom bonded thereto include 1 to 5, preferably 1 to 3, selectedfrom the aforementioned substituent group B. When the number of theabove-mentioned substituents is two or more, the respective substituentsmay be the same or different.

R² is preferably a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl,isopropyl, butyl, isobutyl, pentyl) optionally having substituent(s)other than a substituted amino group, a 3- to 10-membered heterocyclicgroup optionally having substituent(s) or an acyl group (wherein whenthe acyl group is —CONR′R″, R′ and R″ are both hydrogen atoms or form,together with the nitrogen atom bonded thereto, a nitrogen-containingheterocycle (e.g., morpholine) optionally having substituent(s)), morepreferably

(1) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl,isobutyl, pentyl) optionally having 1 to 3 substituents selected from

(a) a hydroxy group,

(b) a halogen atom (e.g., fluorine atom),

(c) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy),

(d) a C₁₋₆ alkyl-carbonyloxy group (e.g., acetyloxy),

(e) an aromatic heterocyclic group (e.g., pyridyl) optionally having 1to 3 halogen atoms,

(f) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl), and

(g) a cyclic amino group (e.g., pyrrolidinyl, piperidino, morpholino,thiomorpholino, piperazinyl, imidazolidin-1-yl, pyrazolidin-1-yl etc.)optionally having an oxo group,

(2) a 3- to 10-membered heterocyclic group (1,2,4-triazolyl,1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 4,5-dihydro-1,2,4-oxadiazolyl,tetrazolyl, tetrahydropyrimidinyl, oxazolyl, piperidinyl, pyrrolidinyl,hexahydropyrimidinyl) optionally having 1 to 3 substituents selectedfrom a C₁₋₆ alkyl group and an oxo group,(3) a carboxy group,(4) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, tert-butoxycarbonyl) optionally having 1 to 3substituents selected from a nonaromatic heterocyclic group (e.g.,dioxolyl) optionally having 1 to 3 substituents selected from a C₁₋₆alkyl group (e.g., methyl) and oxo group,(5) a C₁₋₆ alkyl-carbonyl group (e.g., acetyl), or(6) the formula: —CO—NR′R″ wherein R′ and R″ are each a hydrogen atom,or R′ and R″ form, together with the nitrogen atom bonded thereto, anitrogen-containing heterocycle (e.g., azetidine, morpholine,pyrrolidine, piperidine, 7-aza-bicyclo[2.2.1]heptane, homomorpholine,dihydrobenzoxazin (e.g., 3,4-dihydro-2H-1,4-benzoxazin)) optionallyhaving 1 to 3 substituents selected from halogen atom(s) (e.g., fluorineatom).R³

In the formula (II), R³ is an alkyl group optionally substituted bygroup(s) other than a heterospiro ring optionally having substituent(s),an alkenyl group optionally having substituent(s), a cycloalkyl groupoptionally having substituent(s), an alkylthio group optionally havingsubstituent(s), an alkylsulfinyl group optionally having substituent(s),an alkylsulfonyl group optionally having substituent(s), an alkoxy groupoptionally having substituent(s), an aryl group optionally havingsubstituent(s) or a heteroaryl group optionally having substituent(s).

Examples of the “heterospiro ring” of the “alkyl group optionallysubstituted by group(s) other than a heterospiro ring optionally havingsubstituent(s)” for R³ include a spiro ring formed from a 4- to7-membered (preferably 5- or 6 membered) monocyclic non-aromaticheterocycle containing, as a ring constituting atom besides carbon atom,1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and anitrogen atom and a C₃₋₁₀ cycloalkane (as the C₃₋₁₀ cycloalkane, a ringcorresponding to the above-mentioned C₃₋₁₀ cycloalkyl can be mentioned,which is optionally condensed with a benzene ring), a spiro ring formedfrom the monocyclic non-aromatic heterocycles, and the like.

Examples of the “heterospiro ring” include a spiro ring formed from a 4-to 7-membered (preferably 5- or 6-membered) monocyclic non-aromaticheterocycle such as pyrrolidine, piperidine, morpholine, thiomorpholine,piperazine, hexamethylenimine, oxazolidine, thiazolidine, imidazolidine,oxazoline, thiazoline, imidazoline, dioxole (e.g., 1,3-dioxole),dioxolane (e.g., 1,3-dioxolane), dihydrooxadiazole (e.g.,4,5-dihydro-1,2,4-oxadiazole), 2-thioxo-1,3-oxazolidine, pyran,tetrahydropyran, thiopyran, tetrahydrothiopyran,1-oxidetetrahydrothiopyran, 1,1-dioxidetetrahydrothiopyran,tetrahydrofuran, pyrazolidine, pyrazoline, tetrahydropyrimidine,dihydrotriazole (e.g., 2,3-dihydro-1H-1,2,3-triazole),tetrahydrotriazole (e.g., 2,3,4,5-tetrahydro-1H-1,2,3-triazole) and thelike, and a C₃₋₁₀ cycloalkane such as cyclopropane, cyclobutane,cyclopentane, cyclohexane, cycloheptane, cyclooctane and the like or afused ring (e.g., indane, tetrahydronaphthalene, fluorene etc.) formedfrom the C₃₋₁₀ cycloalkane and benzene ring; or a spiro ring formed fromthe monocyclic non-aromatic heterocycles, a spiro ring formed frompyrrolidine, piperidine, morpholine, thiomorpholine, piperazine and thelike and, cyclopropane, cyclobutane, cyclopentane, cyclohexane, indane,tetrahydronaphthalene and the like is preferable.

As the “heterospiro ring”, spiro[indane-1,4′-piperidine] and the likecan be specifically mentioned.

As the substituent of the “heterospiro ring”, 1 to 5, preferably 1 to 3,selected from the aforementioned substituent group A can be mentioned.When the number of the substituents is two or more, the respectivesubstituents may be the same or different.

The “alkyl group” of the “alkyl group optionally substituted by group(s)other than a heterospiro ring optionally having substituent(s)” for R³optionally has (for example, 1 to 5, preferably 1 to 3) substituent(s)other than the “heterospiro ring optionally having substituent(s)” atsubstitutable position(s). When the number of the substituents is two ormore, the respective substituents may be the same or different. Examplesof the substituent include the aforementioned substituent group A.

Examples of the substituent of the “alkenyl group optionally havingsubstituent(s)”, “cycloalkyl group optionally having substituent(s)”,“alkylthio group optionally having substituent(s)”, “alkylsulfinyl groupoptionally having substituent(s)”, “alkylsulfonyl group optionallyhaving substituent(s)”, “alkoxy group optionally having substituent(s)”,“aryl group optionally having substituent(s)” and “heteroaryl groupoptionally having substituent(s)” for R³ include 1 to 5, preferably 1 to3, selected from the aforementioned substituent group A. When the numberof the substituents is two or more, the respective substituents may bethe same or different.

R³ is preferably a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy) optionallyhaving substituent(s), a C₁₋₆ alkylthio group (e.g., methylthio)optionally having substituent(s), a C₃₋₁₀ cycloalkyl group (e.g.,cyclopropyl) optionally having substituent(s), an aryl (e.g., phenyl)group optionally having substituent(s), or a heteroaryl group (e.g.,thienyl) optionally having substituent(s), more preferably, a C₁₋₆alkoxy group (e.g., methoxy, ethoxy) optionally substituted by a C₁₋₆alkoxy group (e.g., methoxy, ethoxy) or a halogen atom (e.g., fluorineatom), a C₁₋₆ alkylthio group (e.g., methylthio), a C₃₋₁₀ cycloalkylgroup (e.g., cyclopropyl) optionally substituted by a C₁₋₆ alkyl group(e.g., methyl), an aryl group (e.g., phenyl) or a heteroaryl group(e.g., thienyl, thiazolyl, pyridyl, pyrazolyl, imidazolyl,1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl) optionally substituted by a C₁₋₆alkyl group (e.g., methyl), more preferably, a C₁₋₆ alkoxy group (e.g.,methoxy, ethoxy) optionally having substituent(s).

X

In the formula (I), X is absent or a hydrogen atom, an alkyl groupoptionally substituted by group(s) other than a heterospiro ringoptionally having substituent(s) or a cycloalkyl group optionally havingsubstituent(s).

Examples of the “heterospiro ring optionally having substituent(s)” ofthe “alkyl group optionally substituted by group(s) other than aheterospiro ring optionally having substituent(s)” for X include thosesimilar to the “heterospiro ring optionally having substituent(s)” ofthe aforementioned “C₁₋₆ alkyl group optionally substituted by group(s)other than a heterospiro ring optionally having substituent(s)” for R³.

The “alkyl group” of the “alkyl group optionally substituted by group(s)other than a heterospiro ring optionally having substituent(s)” for Xoptionally has (for example, 1 to 5, preferably 1 to 3) substituent(s)other than the heterospiro ring optionally having substituent(s) atsubstitutable position(s). When the number of the substituents is two ormore, the respective substituents may be the same or different. Examplesof the substituent include a halogen atom, a hydroxy group, an alkenylgroup optionally having substituent(s), an alkynyl group optionallyhaving substituent(s), a cycloalkyl group optionally havingsubstituent(s), a cycloalkyloxy group optionally having substituent(s),an alkylthio group optionally having substituent(s), an alkylsulfinylgroup optionally having substituent(s), an alkylsulfonyl groupoptionally having substituent(s), an alkoxy group optionally havingsubstituent(s), an aryl group optionally having substituent(s), aheteroaryl group optionally having substituent(s), an aryloxy groupoptionally having substituent(s), and an acyl group.

Examples of the substituent of the “alkenyl group optionally havingsubstituent(s)”, “alkynyl group optionally having substituent(s)”,“cycloalkyl group optionally having substituent(s)”, “cycloalkyloxygroup optionally having substituent(s)”, “alkylthio group optionallyhaving substituent(s)”, “alkylsulfinyl group optionally havingsubstituent(s)”, “alkylsulfonyl group optionally having substituent(s)”,“alkoxy group optionally having substituent(s)”, “aryl group optionallyhaving substituent(s)”, “heteroaryl group optionally havingsubstituent(s)” and “aryloxy group optionally having substituent(s)”exemplified as the “substituent” of the “alkyl group optionallysubstituted by group(s) other than a heterospiro ring optionally havingsubstituent(s)” for X include 1 to 5, preferably 1 to 3, selected fromthe aforementioned substituent group A. When the number of thesubstituents is two or more, the respective substituents may be the sameor different.

Examples of the substituent of the “cycloalkyl group optionally havingsubstituent(s)” for X include 1 to 5, preferably 1 to 3, selected fromthe aforementioned substituent group A. When the number of thesubstituents is two or more, the respective substituents may be the sameor different.

X is preferably

(1) a hydrogen atom;

(2) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl,hexyl) optionally substituted by 1 to 3 substituents selected from

(a) a halogen atom (e.g., fluorine atom),

(b) a hydroxy group,

(c) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy) optionally having a C₁₋₆alkoxy group (e.g., methoxy) or a halogen atom (e.g., fluorine atom),

(d) a C₁₋₆ alkylthio group (e.g., methylthio),

(e) an aryl group (e.g., phenyl),

(f) a aryloxy group (e.g., phenyloxy) optionally having a C₁₋₆ alkoxygroup (e.g., methoxy) or a halogen atom (e.g., fluorine atom), and

(g) a heteroaryl group (e.g., thienyl, thiazolyl); or

(3) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl), more preferably, aC₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl)optionally substituted by a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy).

X¹

In the formula (II), X¹ is a C₁₋₆ alkylene group optionally substitutedby group(s) other than a heterospiro ring optionally havingsubstituent(s).

Examples of the “heterospiro ring optionally having substituent(s)” ofthe “C₁₋₆ alkylene group optionally substituted by group(s) other than aheterospiro ring optionally having substituent(s)” for X¹ include thosesimilar to the “heterospiro ring optionally having substituent(s)” ofthe aforementioned “C₁₋₆ alkyl group optionally substituted by group(s)other than a heterospiro ring optionally having substituent(s)” for R³.

The “C₁₋₆ alkylene group” of the “C₁₋₆ alkylene group optionallysubstituted by group(s) other than a heterospiro ring optionally havingsubstituent(s)” for X¹ optionally has (for example, 1 to 5, preferably 1to 3) substituent(s) other than a heterospiro ring optionally havingsubstituent(s) at substitutable position(s). When the number of thesubstituents is two or more, the respective substituents may be the sameor different. Examples of the substituent include the aforementionedsubstituent group A.

X¹ is preferably a “C₁₋₆ alkylene group optionally substituted bygroup(s) other than a heterospiro ring optionally having substituent(s)and an oxo group”, more preferably, a C₁₋₆ alkylene group (e.g.,methylene, ethylene, trimethylene, tetramethylene).

Ring A and ring A¹

In the formula (I), ring A is a heterocycle optionally havingsubstituent(s), and in the formula (II), ring A¹ is a fused heterocycleoptionally having substituent(s). However, ring A is not

wherein —X is as defined above, ring C is a heterocycle optionallyhaving substituent(s), ring D is a benzene ring optionally havingsubstituent(s), R′″ is a substituted alkyl group or a substituted alkoxygroup and R″″ is a substituent, and ring A¹ is not

wherein ring C is a heterocycle optionally having substituent(s), ring Dis a benzene ring optionally having substituent(s), R′″ is a substitutedalkyl group or a substituted alkoxy group, R″″ is a substituent, andother symbols are as defined above.

More preferably, the “heterocycle” of the “heterocycle optionally havingsubstituent(s)” for ring A and the “fused heterocycle” of the “fusedheterocycle optionally having substituent(s)” for ring A¹ are not thefollowing rings.

whereinR^(1a) is an optionally substituted C₁₋₆ alkyl group, a C₃₋₆ cycloalkoxygroup substituted by C₁₋₄ alkoxy, an optionally substituted C₂₋₆ alkenylgroup, an optionally substituted C₂₋₆ alkenyloxy group, an optionallysubstituted C₃₋₆ alkynyl group, an optionally substituted C₃₋₆alkynyloxy group, an optionally substituted C₁₋₆ alkylsulfinyl group, anoptionally substituted C₁₋₆ alkylsulfonyl group, an optionallysubstituted C₁₋₆ alkoxy group, an optionally substituted amino group, anoptionally substituted aminocarbonyl group, an optionally substitutedC₁₋₄ alkoxycarbonyl group or an optionally substituted C₁₋₄alkylcarbonyl group;R^(1b) and R^(1e) are the same or different and each independently is ahydrogen atom, a cyano group, an optionally substituted C₁₋₈ alkylgroup, an optionally substituted C₁₋₆ alkoxy group, an optionallysubstituted C₂₋₆ alkenyl group, C₁₋₆ alkylsulfonyl group, or a halogenatom;

R^(1c) and R^(1d) are the same or different and each independently is ahydrogen atom, a halogen atom, a hydroxyl group, a formyl group, acarboxy group, a cyano group, an optionally substituted C₁₋₆ alkylgroup, an optionally substituted C₂₋₆ alkenyl group, an optionallysubstituted C₂₋₆ alkynyl group, an optionally substituted C₃₋₁₀cycloalkyl group, an optionally substituted C₅₋₆ cycloalkenyl group, anoptionally substituted C₆₋₁₀ aryl group, an optionally substituted C₇₋₁₄aralkyl group, an optionally substituted 5-membered to 10-memberedmonocyclic or polycyclic heteroaryl group, an optionally substituted5-membered or 6-membered saturated heterocyclic group, an optionallysubstituted C₁₋₆ alkylthio group, an optionally substituted C₁₋₆alkylsulfinyl group, an optionally substituted C₁₋₆ alkylsulfonyl group,an optionally substituted C₆₋₁₀ arylthio group, an optionallysubstituted C₆₋₁₀ arylsulfinyl group, an optionally substituted C₆₋₁₀arylsulfonyl group, an optionally substituted C₁₋₆ alkoxy group, anoptionally substituted C₃₋₆ alkynyloxy group, an optionally substitutedC₃₋₁₀ cycloalkyloxy group, an optionally substituted C₆₋₁₀ aryloxygroup, an optionally substituted C₇₋₁₄ aralkyloxy group, an optionallysubstituted 5-membered to 10-membered monocyclic or polycyclicheteroaryloxy group, an optionally substituted amino group, anoptionally substituted aminocarbonyl group, an optionally substitutedaminosulfonyl group, an optionally substituted C₁₋₄ alkoxycarbonylgroup, an optionally substituted C₃₋₁₀ cycloalkyloxycarbonyl group, anoptionally substituted C₁₋₄ alkylcarbonyl group, an optionallysubstituted C₃₋₁₀ cycloalkylcarbonyl group, an optionally substitutedC₆₋₁₀ arylcarbonyl group or an optionally substituted 5-membered to10-membered monocyclic or polycyclic heteroarylcarbonyl group; R^(1f) isa hydrogen atom, a halogen atom, a cyano group, an optionallysubstituted C₃₋₆ cycloalkyl group, an optionally substituted C₂₋₆alkenyl group, an optionally substituted C₂₋₆ alkenyloxy group, anoptionally substituted C₃₋₆ alkynyl group, an optionally substitutedC₃₋₆ alkynyloxy group, an optionally substituted C₃₋₁₀ cycloalkyloxygroup, an optionally substituted C₁₋₆ alkoxy group or an optionallysubstituted C₁₋₆ alkyl group; R^(1a′) is a hydrogen atom, a halogenatom, a hydroxyl group, a formyl group, a carboxy group, a cyano group,an optionally substituted C₁₋₆ alkyl group, an optionally substitutedC₂₋₆ alkenyl group, an optionally substituted C₂₋₆ alkynyl group, anoptionally substituted C₃₋₆ cycloalkyl group, a C₁₋₆ alkylthio group,C₁₋₆ alkylsulfonyl group, a C₁₋₆ alkoxy group optionally substituted bya halogen atom, C₁₋₄ alkoxy or C₃₋₆ cycloalkyl, an optionallysubstituted C₃₋₆ cycloalkoxy group, an optionally substituted aminogroup, an aminocarbonyl group, a C₁₋₄ alkoxycarbonyl group, a C₁₋₄alkylcarbonyl group, an optionally substituted C₆₋₁₀ aryl group, anoptionally substituted C₆₋₁₀ aryloxy group or an optionally substitutedC₇₋₁₄ aralkyloxy group;

or R^(1a′) is a hydrogen atom; R^(1b′) and R^(1c′) in combination form afused ring with a benzene ring, which contains at least one hetero atom

wherein R^(1a) is an optionally substituted C₁₋₆ alkyl group, anoptionally substituted C₂₋₆ alkenyl group, an optionally substitutedC₂₋₆ alkynyl group, an optionally substituted C₃₋₁₀ cycloalkyl group, anoptionally substituted C₅₋₆ cycloalkenyl group or an optionallysubstituted 5-membered to 10-membered monocyclic or polycyclicheteroaryl-C₁₋₄ alkyl group; R^(1b), R^(1c), R^(1d) and R^(1e) are thesame or different and each independently is a hydrogen atom, a halogenatom, a hydroxyl group, a formyl group, a carboxy group, a cyano group,an optionally substituted C₁₋₆ alkyl group, an optionally substitutedC₂₋₆ alkenyl group, an optionally substituted C₂₋₆ alkynyl group, anoptionally substituted C₃₋₁₀ cycloalkyl group, an optionally substitutedC₅₋₆ cycloalkenyl group, an optionally substituted C₆₋₁₀ aryl group, anoptionally substituted C₇₋₁₄ aralkyl group, an optionally substituted5-membered to 10-membered monocyclic or polycyclic heteroaryl group, anoptionally substituted 5-membered to 10-membered monocyclic orpolycyclic heteroaryl C₁₋₄ alkyl group, an optionally substitutedsaturated heterocyclic group, an optionally substituted C₁₋₆ alkylthiogroup, an optionally substituted C₁₋₆ alkylsulfinyl group, an optionallysubstituted C₁₋₆ alkylsulfonyl group, an optionally substituted C₆₋₁₀arylthio group, an optionally substituted C₆₋₁₀ arylsulfinyl group, anoptionally substituted C₆₋₁₀ arylsulfonyl group, an optionallysubstituted C₁₋₆ alkoxy group, an optionally substituted C₃₋₆ alkynyloxygroup, an optionally substituted C₃₋₆ cycloalkyloxy group, an optionallysubstituted C₆₋₁₀ aryloxy group, an optionally substituted C₇₋₁₄aralkyloxy group, an optionally substituted 5-membered to 10-memberedmonocyclic or polycyclic heteroaryloxy group, an optionally substituted5-membered to 10-membered monocyclic or polycyclic heteroaryl C₁₋₄alkyloxy group, an optionally substituted amino group, an optionallysubstituted aminocarbonyl group, an optionally substitutedaminocarbonyloxy group, an optionally substituted aminosulfonyl group,an optionally substituted C₁₋₆ alkoxycarbonyl group, an optionallysubstituted C₃₋₆ cycloalkyloxycarbonyl group, an optionally substitutedC₁₋₄ alkylcarbonyl group, an optionally substituted C₃₋₆cycloalkylcarbonyl group, an optionally substituted C₆₋₁₀ arylcarbonylgroup or an optionally substituted 5-membered to 10-membered monocyclicor polycyclic heteroarylcarbonyl group; R^(1f) is a hydrogen atom, ahalogen atom, a hydroxyl group, a cyano group, an optionally substitutedC₁₋₆ alkyl group, an optionally substituted C₂₋₆ alkenyl group, anoptionally substituted C₂₋₆ alkynyl group, an optionally substitutedC₃₋₁₀ cycloalkyl group, an optionally substituted C₅₋₆ cycloalkenylgroup, an optionally substituted C₆₋₁₀ aryl group, an optionallysubstituted C₇₋₁₄ aralkyl group, an optionally substituted 5-membered to10-membered monocyclic or polycyclic heteroaryl group, an optionallysubstituted 5-membered to 10-membered monocyclic or polycyclicheteroaryl C₁₋₄ alkyl group, an optionally substituted saturatedheterocyclic group, an optionally substituted C₁₋₆ alkylthio group, anoptionally substituted C₁₋₆ alkylsulfinyl group, an optionallysubstituted C₁₋₆ alkylsulfonyl group, an optionally substituted C₁₋₆alkoxy group, an optionally substituted C₃₋₆ alkynyloxy group, anoptionally substituted C₃₋₆ cycloalkyloxy group, an optionallysubstituted C₆₋₁₀ aryloxy group, an optionally substituted C₇₋₁₄aralkyloxy group, an optionally substituted 5-membered to 10-memberedmonocyclic or polycyclic heteroaryl C₁₋₄ alkyloxy group, an optionallysubstituted amino group, an optionally substituted aminocarbonyl group,an optionally substituted aminosulfonyl group, an optionally substitutedC₁₋₄ alkoxycarbonyl group, an optionally substituted C₃₋₆cycloalkyloxycarbonyl group, an optionally substituted C₁₋₄alkylcarbonyl group, an optionally substituted C₃₋₆ cycloalkylcarbonylgroup, an optionally substituted C₆₋₁₀ arylcarbonyl group or anoptionally substituted 5-membered to 10-membered monocyclic orpolycyclic heteroarylcarbonyl group.

wherein R^(1a) is an optionally substituted C₁₋₆ alkyl group, anoptionally substituted C₂₋₁₀ alkenyl group, an optionally substitutedC₂₋₆ alkynyl group, an optionally substituted C₃₋₆ cycloalkyl group, anoptionally substituted C₅₋₆ cycloalkenyl group, an optionallysubstituted C₁₋₆ alkylsulfinyl group, an optionally substituted C₁₋₆alkylsulfonyl group, an optionally substituted aminocarbonyl group, anoptionally substituted C₁₋₄ alkoxycarbonyl group or an optionallysubstituted C₁₋₄ alkylcarbonyl group;R^(1b) and R^(1e) are the same or different and each independently is ahydrogen atom, a halogen atom, a cyano group, an optionally substitutedC₁₋₆ alkyl group, an optionally substituted C₁₋₆ alkoxy group, anoptionally substituted C₃₋₆ cycloalkyloxy group or an optionallysubstituted aminocarbonyl group;R^(1c) and R^(1d) are the same or different and each independently is ahydrogen atom, a halogen atom, a hydroxyl group, a formyl group, acarboxy group, a cyano group, an optionally substituted C₁₋₆ alkylgroup, an optionally substituted C₂₋₆ alkenyl group, an optionallysubstituted C₂₋₆ alkynyl group, an optionally substituted C₃₋₁₀cycloalkyl group, an optionally substituted C₅₋₆ cycloalkenyl group, anoptionally substituted C₆₋₁₀ aryl group, an optionally substituted C₇₋₁₄aralkyl group, an optionally substituted 5-membered to 10-memberedmonocyclic or polycyclic heteroaryl group, an optionally substituted5-membered to 10-membered monocyclic or polycyclic heteroaryl C₁₋₄ alkylgroup, an optionally substituted saturated heterocyclic group, anoptionally substituted C₁₋₆ alkylthio group, an optionally substitutedC₁₋₆ alkylsulfinyl group, an optionally substituted C₁₋₆ alkylsulfonylgroup, an optionally substituted C₆₋₁₀ arylthio group, an optionallysubstituted C₆₋₁₀ arylsulfinyl group, an optionally substituted C₆₋₁₀arylsulfonyl group, an optionally substituted C₁₋₆ alkoxy group, anoptionally substituted C₃₋₆ alkynyloxy group, an optionally substitutedC₃₋₁₀ cycloalkyloxy group, an optionally substituted C₆₋₁₀ aryloxygroup, an optionally substituted C₇₋₁₄ aralkyloxy group, an optionallysubstituted 5-membered to 10-membered monocyclic or polycyclicheteroaryloxy group, an optionally substituted 5-membered to 10-memberedmonocyclic or polycyclic heteroaryl C₁₋₄ alkyloxy group, an optionallysubstituted amino group, an optionally substituted aminocarbonyl group,an optionally substituted aminosulfonyl group, an optionally substitutedC₁₋₄ alkoxycarbonyl group, an optionally substituted C₃₋₆cycloalkyloxycarbonyl group, an optionally substituted C₁₋₄alkylcarbonyl group, an optionally substituted C₃₋₆ cycloalkylcarbonylgroup, an optionally substituted C₆₋₁₀ arylcarbonyl group or anoptionally substituted 5-membered to 10-membered monocyclic orpolycyclic heteroarylcarbonyl group; R^(1f) is a hydrogen atom, ahalogen atom, a cyano group, an optionally substituted C₁₋₆ alkyl group,an optionally substituted C₁₋₆ alkoxy group, an optionally substitutedC₃₋₁₀ cycloalkyl group, an optionally substituted C₂₋₆ alkenyl group, anoptionally substituted C₂₋₆ alkenyloxy group, an optionally substitutedC₃₋₆ alkynyl group, an optionally substituted C₃₋₆ alkynyloxy group oran optionally substituted C₃₋₁₀ cycloalkyloxy group.

Examples of the substituent of the “heterocycle optionally havingsubstituent(s)” for ring A and the “fused heterocycle optionally havingsubstituent(s)” for ring A¹ include 1 to 5, preferably 1 to 3, selectedfrom the aforementioned substituent group A. When the number of thesubstituents is two or more, the respective substituents may be the sameor different.

Ring A is preferably a monocyclic heterocycle such as pyrimidine,pyrrole, imidazole, pyrazole or triazole (1,2,3-triazole,1,2,4-triazole) and the like; or a fused heterocycle such as indole,benzimidazole, 1H-pyrrolo[1,2-b]pyridine, 3H-imidazo[4,5-b]pyridine,imidazo[1,2-a]pyridine, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine,4,5,6,7-tetrahydro-1H-indole, 4,5,6,7-tetrahydro-1H-benzimidazole,1,4-dihydrocyclopenta[b]pyrrole, 1,4-dihydropyrrolo[3,2-b]pyrrole,4H-furo[3,2-b]pyrrole, 4H-thieno[3,2-b]pyrrole,1,4-dihydrocyclopentaimidazole, 1,4-dihydropyrrolo[2,3-d]imidazole,1H-furo[2,3-d]imidazole or 1H-thieno[2,3-d]imidazole,imidazo[1,2-a]pyrimidine, imidazo[1,2-a]pyrazine,imidazo[1,2-c]pyrimidine, imidazo[1,2-b]pyridazine, benzofuran,benzothiophene, benzothiazole, quinoline, isoquinoline and the like,each of which optionally has 1 to 5, preferably 1 to 3, substituent(s)selected from substituent group A.

Preferable ring A¹ is a fused heterocycle selected from ring A.

Each of ring A and ring A¹ is more preferably a ring represented by anyof the formulas

wherein R^(a) and R^(b) are each independently a hydrogen atom, ahalogen atom (e.g., fluorine atom, chlorine atom), an alkyl groupoptionally having substituent(s), an alkoxy group (e.g., methoxy)optionally having substituent(s), or an acyl group (e.g., C₁₋₆alkoxy-carbonyl) (particularly preferably a hydrogen atom);R^(c) is a hydrogen atom, a halogen atom (e.g., fluorine atom, chlorineatom), ═O, ═S, an alkyl group optionally having substituent(s), analkoxy (e.g., methoxy) group optionally having substituent(s), or anacyl group (e.g., C₁₋₆ alkoxy-carbonyl);Y¹ and Y² are each independently CH or N; andZ is CH₂, NH, O or S, more preferably a ring represented by

wherein Y¹, Y², R^(a) and R^(b) are as defined above.

Examples of the substituent of the “alkyl group optionally havingsubstituent(s)” and “alkoxy group optionally having substituent(s)” forR^(a), R^(b) or R^(c) include 1 to 5, preferably 1 to 3, selected fromthe aforementioned substituent group B. When the number of thesubstituents is two or more, the respective substituents may be the sameor different.

Each of ring A and ring A¹ is more preferably a ring represented by anyof the formulas

wherein R^(a) and R^(b) are each independently a hydrogen atom, ahalogen atom (e.g., fluorine atom, chlorine atom), a C₁₋₆ alkoxy group(e.g., methoxy), or a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl)(particularly preferably a hydrogen atom);R^(c) is a hydrogen atom or ═O;Y¹ and Y² are each independently CH or N; andZ is S, more preferably, a ring represented by

wherein R^(a) and R^(b) are each independently a hydrogen atom, ahalogen atom (e.g., fluorine atom, chlorine atom), a C₁₋₆ alkoxy group(e.g., methoxy), or a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl)(particularly preferably a hydrogen atom); andY¹ and Y² are each independently CH or N, more preferably,

Ring B

In the formula (II), ring B is a 5- to 7-membered nitrogen-containingheterocycle optionally having substituent(s), n is 0, 1 or 2 and NHconstituting ring B is unsubstituted.

Examples of the substituent of the “5- to 7-membered nitrogen-containingheterocycle optionally having substituent(s)” for ring B include 1 to 5,preferably 1 to 3, selected from the aforementioned substituent group Aor two substituents bonded to the carbon atoms adjacent to ring B may bebonded to form C₃₋₁₀ cycloalkane (e.g., cyclopentane, cyclohexane) to becondensed with ring B. When the number of the substituents is two ormore, the respective substituents may be the same or different.

Ring B is preferably a 6-membered (n=1) nitrogen-containing heterocycleoptionally having 1 to 5, preferably 1 to 3, substituents selected fromsubstituent group A, more preferably, the formula

more preferably, a ring represented by the formula

wherein R⁴ isa hydrogen atom,a halogen atom,a hydroxy group,a cyano (nitrile) group,an amino group optionally having substituent(s),a mercapto group optionally having a substituent (the mercapto group isoptionally oxidized)an alkyl group optionally having substituent(s) other than a substitutedamino group,an alkoxy group optionally having substituent(s),a 3- to 10-membered cyclic hydrocarbon group optionally havingsubstituent(s),a 3- to 10-membered heterocyclic group optionally having substituent(s)oran acyl group (wherein when the acyl group is —CONR′R″, thenR′ and R″ are both hydrogen atoms or form, together with the nitrogenatom bonded thereto, a nitrogen-containing heterocycle optionally havingsubstituent(s)).

The “alkyl group” of the “alkyl group optionally having substituent(s)other than a substituted amino group” for R⁴ optionally has (forexample, 1 to 5, preferably 1 to 3) substituent(s) other than thesubstituted amino group at substitutable position(s). When the number ofthe substituents is two or more, the respective substituents may be thesame or different. Examples of the substituent include substituent groupB (except mono- or di-C₁₋₆ alkylamino group, C₇₋₁₆ aralkylamino group,C₁₋₆ alkoxy-carbonylamino group and C₁₋₆ alkyl-carbonylamino group).Examples of the “substituent” of the “substituted amino group” includeunsubstituted or substituted alkyl, unsubstituted or substitutedalkenyl, unsubstituted or substituted alkynyl, unsubstituted orsubstituted aryl, unsubstituted or substituted heterocyclyl orunsubstituted or substituted cycloalkyl or acyl (e.g., C₁₋₆ alkyl groupsubstituted by C₁₋₆ cycloalkyl group or heterocycle) and the like.

Examples of the substituent of the “alkoxy group optionally havingsubstituent(s)”, “3- to 10-membered cyclic hydrocarbon group optionallyhaving substituent(s)” and “3- to 10-membered heterocyclic groupoptionally having substituent(s)” for R⁴ include 1 to 5, preferably 1 to3, selected from the aforementioned substituent group B. When the numberof the substituents is two or more, the respective substituents may bethe same or different.

Examples of the “substituent” of the “amino group optionally havingsubstituent(s)” for R⁴ include 1 or 2 selected from the aforementionedsubstituent group B. When the number of the substituents is two, therespective substituents may be the same or different.

Examples of the “substituent” of the “mercapto group optionally having asubstituent” for R⁴ include the aforementioned substituent group B. Themercapto group may be oxidized by 1 or 2 oxygens.

Examples of the substituent of the “nitrogen-containing heterocycleoptionally having substituent(s)” formed by R′ and R″, together with thenitrogen atom include 1 to 5, preferably 1 to 3, selected from theaforementioned substituent group B. When the number of theabove-mentioned substituents is two or more, the respective substituentsmay be the same or different.

Ring B is more preferably a ring represented by the formula

wherein R⁴ isa hydrogen atom,a halogen atom,a hydroxy group,a cyano (nitrile) group,an amino group optionally having 1 or 2 substituents selected from thesubstituent group B,a mercapto group optionally having a substituent selected from thesubstituent group B (the mercapto group is optionally oxidized),a C₁₋₆ alkyl group optionally having 1 or 2 substituents selected fromthe substituent group B,a C₁₋₆ alkoxy group optionally having a substituent selected from thesubstituent group B,a 3- to 10-membered cyclic hydrocarbon group optionally having 1 to 3substituents selected from the substituent group B, a 3- to 10-memberedheterocyclic group optionally having 1 to 3 substituents selected fromthe substituent group B, a carboxy group,a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, tert-butoxycarbonyl) optionally having 1 to 3substituents selected from the substituent group B, ora group represented by the formula: —CONR′R″wherein R′ and R″ are each a hydrogen atom, or R′ and R″ form, togetherwith the nitrogen atom bonded thereto, a nitrogen-containing heterocycleoptionally having 1 to 3 substituents selected from the aforementionedsubstituent group B.

Ring B is more preferably a ring represented by

wherein R⁴ is(1) a hydrogen atom,(2) a cyano (nitrile) group,(3) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl,isobutyl, pentyl) optionally having 1 to 3 substituents selected from(a) a hydroxy group,(b) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy),(c) a C₁₋₆ alkyl-carbonyloxy group (e.g., acetyloxy),(d) an aromatic heterocyclic group (e.g., pyridyl, pyrazolyl, triazolyl)optionally having 1 to 3 halogen atoms,(e) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl), and(f) a cyclic amino group (e.g., pyrrolidinyl, piperidino, morpholino,thiomorpholino, piperazinyl, imidazolidin-1-yl, pyrazolidin-1-yl etc.)optionally having an oxo group,(4) a 3- to 10-membered heterocyclic group (1,2,4-triazolyl,1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 4,5-dihydro-1,2,4-oxadiazolyl,tetrazolyl, tetrahydropyrimidinyl, oxazolyl, piperidinyl, pyrrolidinyl,hexahydropyrimidinyl) optionally having 1 to 3 substituents selectedfrom a C₁₋₆ alkyl group and an oxo group,(5) a carboxy group,(6) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, tert-butoxycarbonyl) optionally having 1 to 3substituents selected from a nonaromatic heterocyclic group (e.g.,dioxolyl) optionally having 1 to 3 substituents selected from a C₁₋₆alkyl group (e.g., methyl) and oxo group, or(7) a group represented by the formula: —CO—NR′R″wherein R′ and R″ are each a hydrogen atom, or form, together with thenitrogen atom bonded thereto, a nitrogen-containing heterocycle (e.g.,azetidine, morpholine, pyrrolidine, piperidine,7-aza-bicyclo[2.2.1]heptane, homomorpholine, dihydrobenzoxazine (e.g.,3,4-dihydro-2H-1,4-benzoxazine)) optionally having 1 to 3 substituentsselected from halogen atom(s) (e.g., fluorine atom).

Preferable examples of compound (I) include the following.

[Compound I-1]

A compound represented by the formula (I) wherein ring A is a ringrepresented by

wherein R^(a) and R^(b) are each independently a hydrogen atom, ahalogen atom, an alkyl group optionally having substituent(s), an alkoxygroup optionally having substituent(s) or an acyl group (particularlypreferably a hydrogen atom);Y¹ and Y² are each independently CH or N,R¹ is a C₁₋₆ alkyl group optionally having substituent(s),R² is a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl,isobutyl, pentyl) optionally having substituent(s) other than asubstituted amino group or an acyl group (wherein when the acyl group is—CONR′R″, then R′ and R″ are both hydrogen atoms or form, together withthe nitrogen atom bonded thereto, a nitrogen-containing heterocycle(e.g., morpholine) optionally having substituent(s)), andX is a C₁₋₆ alkyl group optionally substituted by an alkoxy group (e.g.,methoxy, ethoxy), or a salt thereof.

Here, examples of the substituent of the “C₁₋₆ alkyl group optionallyhaving substituent(s)” for R¹ include 1 to 5, preferably 1 to 3,selected from the aforementioned substituent group A.

Examples of the substituent of the “C₁₋₆ alkyl group optionally havingsubstituent(s)” and “C₁₋₆ alkoxy group optionally having substituent(s)”for R^(a) or R^(b) include 1 to 5, preferably 1 to 3, selected from theaforementioned substituent group B.

Examples of the substituent of the “C₁₋₆ alkyl group optionally havingsubstituent(s) other than a substituted amino group” for R² include 1 to5, preferably 1 to 3, selected from the aforementioned substituent groupB.

Examples of the substituent of the “nitrogen-containing heterocycleoptionally having substituent(s)” formed by R′ and R″ together with thenitrogen atom bonded thereto include 1 to 5, preferably 1 to 3, selectedfrom the aforementioned substituent group B. When the number of theabove-mentioned substituents is two or more, the respective substituentsmay be the same or different.

[Compound I-2]

A compound represented by the formula (II) wherein ring A¹ is a ringrepresented by

wherein R^(a) and R^(b) are each independently a hydrogen atom, ahalogen atom, an alkyl group optionally having substituent(s), an alkoxygroup optionally having substituent(s), or an acyl group (particularlypreferably a hydrogen atom);Y¹ and Y² are each independently CH or N,

ring B is a ring represented by

wherein R⁴ isa hydrogen atom,a halogen atom,a hydroxy group,a cyano (nitrile) group,an amino group optionally having substituent(s),a mercapto group optionally having a substituent (the mercapto group isoptionally oxidized),an alkyl group optionally having substituent(s),an alkoxy group optionally having substituent(s),a 3- to 10-membered cyclic hydrocarbon group optionally havingsubstituent(s),a 3- to 10-membered heterocyclic group optionally having substituent(s),oran acyl group,R¹ is a C₁₋₆ alkyl group optionally having substituent(s),R³ is a C₁₋₆ alkoxy group optionally having substituent(s), andX¹ is a C₁₋₆ alkylene group, or a salt thereof.

Here, examples of the substituent of the “C₁₋₆ alkyl group optionallyhaving substituent(s)” for R¹ and the “C₁₋₆ alkoxy group optionallyhaving substituent(s)” for R³ include 1 to 5, preferably 1 to 3,selected from the aforementioned substituent group A.

Examples of the substituent of the “C₁₋₆ alkyl group optionally havingsubstituent(s)” and “C₁₋₆ alkoxy group optionally having substituent(s)”for R^(a) or R^(b) include 1 to 5, preferably 1 to 3, selected from theaforementioned substituent group B.

Examples of the substituent of the “C₁₋₆ alkyl group optionally havingsubstituent(s)”, “C₁₋₆ alkoxy group optionally having substituent(s)”,“3- to 10-membered cyclic hydrocarbon group optionally havingsubstituent(s)” and “3- to 10-membered heterocyclic group optionallyhaving substituent(s)” for R⁴ include 1 to 5, preferably 1 to 3,selected from the aforementioned substituent group B. When the number ofthe above-mentioned substituents is two or more, the respectivesubstituents may be the same or different.

Examples of the “substituent” of the “amino group optionally havingsubstituent(s)” for R⁴ include 1 or 2 selected from the aforementionedsubstituent group B. When the number of the above-mentioned substituentsis two, the respective substituents may be the same or different.

Examples of the “substituent” of the “mercapto group optionally having asubstituent” for R⁴ include the aforementioned substituent group B. Themercapto group may be oxidized by 1 or 2 oxygens.

[Compound I-3]

A compound represented by the formula (II) wherein ring A¹ is a ringrepresented by

wherein R^(a) and R^(b) are each independently a hydrogen atom, ahalogen atom, an alkyl group optionally having substituent(s), an alkoxygroup optionally having substituent(s) or an acyl group (particularlypreferably a hydrogen atom);Y¹ and Y² are each independently CH or N,

ring B is a ring represented by

wherein R⁴ isa hydrogen atom,a halogen atom,a hydroxy group,a cyano (nitrile) group,an amino group optionally having substituent(s),a mercapto group optionally having a substituent (the mercaptogroup is optionally oxidized),an alkyl group optionally having substituent(s) other than a substitutedamino group,an alkoxy group optionally having substituent(s),a 3- to 10-membered cyclic hydrocarbon group optionally havingsubstituent(s),a 3- to 10-membered heterocyclic group optionally having substituent(s),oran acyl group (wherein when the acyl group is —CONR′R″, then R′ and R″are both hydrogen atoms or form, together with the nitrogen atom bondedthereto, a nitrogen-containing heterocycle optionally havingsubstituent(s)),R¹ is a C₁₋₆ alkyl group optionally having substituent(s),R³ is a C₁₋₆ alkoxy group optionally having substituent(s), andX¹ is a C₁₋₆ alkylene group, or a salt thereof.

Here, Examples of the substituent of the “C₁₋₆ alkyl group optionallyhaving substituent(s)” for R¹ and the “C₁₋₆ alkoxy group optionallyhaving substituent(s)” for R³ include 1 to 5, preferably 1 to 3,selected from the aforementioned substituent group A.

Examples of the substituent of the “C₁₋₆ alkyl group optionally havingsubstituent(s)” and “C₁₋₆ alkoxy group optionally having substituent(s)”for R^(a) or R^(b) include 1 to 5, preferably 1 to 3, selected from theaforementioned substituent group B.

Examples of the substituent of the “C₁₋₆ alkyl group optionally havingsubstituent(s) other than a substituted amino group”, “C₁₋₆ alkoxy groupoptionally having substituent(s)”, “3- to 10-membered cyclic hydrocarbongroup optionally having substituent(s)” and “3- to 10-memberedheterocyclic group optionally having substituent(s)” for R⁴ include 1 to5, preferably 1 to 3, selected from the aforementioned substituent groupB.

Examples of the substituent of the “nitrogen-containing heterocycleoptionally having substituent(s)” formed by R′ and R″ together with thenitrogen atom bonded thereto include 1 to 5, preferably 1 to 3, selectedfrom the aforementioned substituent group B. When the number of theabove-mentioned substituents is two or more, the respective substituentsmay be the same or different.

Examples of the “substituent” of the “amino group optionally havingsubstituent(s)” for R⁴ include 1 or 2 selected from the aforementionedsubstituent group B. When the number of the above-mentioned substituentsis two, the respective substituents may be the same or different.

Examples of the “substituent” of the “mercapto group optionally having asubstituent” for R⁴ include the aforementioned substituent group B. Themercapto group may be oxidized by 1 or 2 oxygens.

[Compound I-4]

A compound represented by the formula (II) wherein ring A¹ is a ringrepresented by any one of

wherein R^(a) and R^(b) are each independently a hydrogen atom, ahalogen atom (e.g., fluorine atom, chlorine atom), a C₁₋₆ alkoxy group(e.g., methoxy), or C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl)(particularly preferably a hydrogen atom);R^(c) is a hydrogen atom, or ═O;Y¹ and Y² are each independently CH or N;Z is S,

ring B is a ring represented by

wherein R⁴ is(1) a hydrogen atom,(2) a cyano (nitrile) group,(3) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl,isobutyl, pentyl) optionally having 1 to 3 substituents selected from(a) a hydroxy group,(b) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy),(c) a C₁₋₆ alkyl-carbonyloxy group (e.g., acetyloxy),(d) an aromatic heterocyclic group (e.g., pyridyl, pyrazolyl, triazolyl)optionally having 1 to 3 halogen atoms,(e) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl), and(f) a cyclic amino group (e.g., pyrrolidinyl, piperidino, morpholino,thiomorpholino, piperazinyl, imidazolidin-1-yl, pyrazolidin-1-yl etc.)optionally having an oxo group,(4) a 3- to 10-membered heterocyclic group (1,2,4-triazolyl,1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 4,5-dihydro-1,2,4-oxadiazolyl,tetrazolyl, tetrahydropyrimidinyl, oxazolyl, piperidinyl, pyrrolidinyl,hexahydropyrimidinyl) optionally having 1 to 3 substituents selectedfrom a C₁₋₆ alkyl group and an oxo group,(5) a carboxy group,(6) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, tert-butoxycarbonyl) optionally having 1 to 3substituents selected from a nonaromatic heterocyclic group (e.g.,dioxolyl) optionally having 1 to 3 substituents selected from a C₁₋₆alkyl group (e.g., methyl) and oxo group or(7) a group represented by the formula: —CO—NR′R″ wherein R′ and R″ areeach a hydrogen atom, or R′ and R″ form, together with the nitrogen atombonded thereto, a nitrogen-containing heterocycle (e.g., azetidine,morpholine, pyrrolidine, piperidine, 7-aza-bicyclo[2.2.1]heptane,homomorpholine, dihydrobenzoxazin (e.g., 3,4-dihydro-2H-1,4-benzoxazin))optionally having 1 to 3 substituents selected from halogen atom(s)(e.g., fluorine atom),R³ is a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy) optionally substitutedby a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy) or a halogen atom (e.g.,fluorine atom), a C₁₋₆ alkylthio group (e.g., methylthio), a C₃₋₁₀cycloalkyl group (e.g., cyclopropyl) optionally substituted by a C₁₋₆alkyl group (e.g., methyl), an aryl group (e.g., phenyl) or a heteroarylgroup (e.g., thienyl, thiazolyl, pyridyl, pyrazolyl, imidazolyl,1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl) optionally substituted by a C₁₋₆alkyl group (e.g., methyl), andX¹ is a C₁₋₆ alkylene group (e.g., methylene, ethylene, trimethylene,tetramethylene), or a salt thereof.[Compound I-5]

A compound represented by the formula (I) wherein ring A is a pyrimidineoptionally having substituent(s), a pyrrole optionally havingsubstituent(s), an imidazole optionally having substituent(s), apyrazole optionally having substituent(s) or a triazole (e.g.,1,2,3-triazole, 1,2,4-triazole) optionally having substituent(s),

R² is

(1) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl,isobutyl, pentyl) optionally having 1 to 3 substituents selected from

(a) a hydroxy group,

(b) a halogen atom (e.g., fluorine atom),

(c) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy),

(d) a C₁₋₆ alkyl-carbonyloxy group (e.g., acetyloxy),

(e) an aromatic heterocyclic group (e.g., pyridyl) optionally having 1to 3 halogen atoms,

(f) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl), and

(g) a cyclic amino group (e.g., pyrrolidinyl, piperidino, morpholino,thiomorpholino, piperazinyl, imidazolidin-1-yl, pyrazolidin-1-yl etc.)optionally having an oxo group,

(2) a 3- to 10-membered heterocyclic group (1,2,4-triazolyl,1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 4,5-dihydro-1,2,4-oxadiazolyl,tetrazolyl, tetrahydropyrimidinyl, oxazolyl, piperidinyl, pyrrolidinyl,hexahydropyrimidinyl) optionally having 1 to 3 substituents selectedfrom a C₁₋₆ alkyl group and an oxo group,(3) a carboxy group,(4) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, tert-butoxycarbonyl) optionally having 1 to 3substituents selected from a nonaromatic heterocyclic group (e.g.,dioxolyl) optionally having 1 to 3 substituents selected from a C₁₋₆alkyl group (e.g., methyl) and oxo group,(5) a C₁₋₆ alkyl-carbonyl group (e.g., acetyl), or(6) a group represented by the formula: —CO—NR′R″wherein R′ and R″ are each a hydrogen atom, or R′ and R″ form, togetherwith the nitrogen atom bonded thereto, a nitrogen-containing heterocycle(e.g., azetidine, morpholine, pyrrolidine, piperidine,7-aza-bicyclo[2.2.1]heptane, homomorpholine, dihydrobenzoxazin (e.g.,3,4-dihydro-2H-1,4-benzoxazin)) optionally having 1 to 3 substituentsselected from halogen atom(s) (e.g., fluorine atom),R¹ is a C₁₋₆ alkyl group (e.g., isobutyl), andX is(1) a hydrogen atom;(2) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl,hexyl) optionally substituted by 1 to 3 substituents selected from(a) a halogen atom (e.g., fluorine atom),(b) a hydroxy group,(c) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy) optionally having a C₁₋₆alkoxy group (e.g., methoxy) or a halogen atom (e.g., fluorine atom),(d) a C₁₋₆ alkylthio group (e.g., methylthio),(e) an aryl group (e.g., phenyl),(f) an aryloxy group (e.g., phenyloxy) optionally having a C₁₋₆ alkoxygroup (e.g., methoxy) or a halogen atom (e.g., fluorine atom), and(g) a heteroaryl group (e.g., thienyl, thiazolyl); or(3) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl), or a salt thereof.

Here, examples of the substituent of the “pyrimidine” of “pyrimidineoptionally having substituent(s)”, “pyrrole” of “pyrrole optionallyhaving substituent(s)”, “imidazole” of “imidazole optionally havingsubstituent(s)”, “pyrazole” of “pyrazole optionally havingsubstituent(s)” and “triazole” of “triazole optionally havingsubstituent(s)” for ring A include 1 to 3 selected from theaforementioned substituent group A.

[Compound I-6]

A compound represented by the formula (I) wherein

R¹ is a C₁₋₆ alkyl group optionally having substituent(s);

R² is an acyl group (wherein when the acyl group is —CONR′R″, then R′and R″ are both hydrogen atoms or form, together with the nitrogen atombonded thereto, a nitrogen-containing heterocycle optionally havingsubstituent(s));

ring A is a ring represented by the formula

wherein R^(a) and R^(b) are each a hydrogen atom; and Y and Y² are eachindependently CH or N, andX is a C₁₋₆ alkyl group optionally substituted by a C₁₋₆ alkoxy group,or a salt thereof.[Compound I-7]

A compound represented by the formula (II) wherein

R¹ is a C₁₋₆ alkyl group optionally having substituent(s),

R³ is a C₁₋₆ alkoxy group optionally having substituent(s),

ring A¹ is a ring represented by the formula

wherein R^(a) and R^(b) are each a hydrogen atom; and Y¹ and Y² are eachindependently CH or N,X¹ is a C₁₋₆ alkylene group, and

ring B is

wherein R⁴ is —CO—NR′R″ wherein R′ and R″ are each a hydrogen atom, orR′ and R″ form, together with the nitrogen atom bonded thereto, anitrogen-containing heterocycle optionally having 1 to 3 substituentsselected from halogen atom(s), or a salt thereof.

Examples of the salts of compound (I) and compound (II) include metalsalts, ammonium salts, salts with organic bases, salts with inorganicacids, salts with organic acids, salts with basic or acidic amino acids,and the like.

Preferable examples of the metal salt include alkali metal salts such assodium salt, potassium salt and the like; alkaline earth metal saltssuch as calcium salt, magnesium salt, barium salt and the like; aluminumsalt and the like.

Preferable examples of the salt with organic base include a salt withtrimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine,ethanolamine, diethanolamine, triethanolamine, cyclohexylamine,dicyclohexylamine, N,N-dibenzylethylenediamine or the like.

Preferable examples of the salt with inorganic acid include a salt withhydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid or the like.

Preferable examples of the salt with organic acid include a salt withformic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaricacid, oxalic acid, tartaric acid, maleic acid, citric acid, succinicacid, malic acid, methanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid or the like.

Preferable examples of the salt with basic amino acid include a saltwith arginine, lysine, ornithine or the like.

Preferable examples of the salt with acidic amino acid include a saltwith aspartic acid, glutamic acid or the like.

Of these, a pharmaceutically acceptable salt is preferable. When thecompound has an acidic functional group, examples thereof includeinorganic salts such as alkali metal salts (e.g., sodium salt, potassiumsalt, etc.), alkaline earth metal salts (e.g., calcium salt, magnesiumsalt, barium salt, etc.) and the like, ammonium salts, and the like.When the compound has a basic functional group, examples thereof includesalts with inorganic acids such as hydrochloric acid, hydrobromic acid,nitric acid, sulfuric acid, phosphoric acid and the like, and salts withorganic acids such as acetic acid, phthalic acid, fumaric acid, oxalicacid, tartaric acid, maleic acid, citric acid, succinic acid,methanesulfonic acid, p-toluenesulfonic acid and the like.

The production methods of compound (I) and compound (II) are shown inthe following.

Compound (I) compound (II) are obtained by, for example, methods shownin the following reaction schemes or a method analogous thereto, or thelike.

Each of compounds (II)-(XXXXI) shown in the reaction schemes may form asalt. Examples of the salt include salts similar to the salts ofcompound (I) and compound (II).

The compound obtained in each step can also be used for the nextreaction directly as the reaction mixture or as a crude product. Inaddition, it can also be isolated from the reaction mixture according toa conventional method, and can be isolated and purified by a knownmethod such as phase transfer, concentration, solvent extraction,fractional distillation, pH conversion, crystallization,recrystallization, chromatography and the like.

The reaction schemes thereof are shown in the following.

Each symbol of the compounds in the schemes is as defined above. R is aC₁₋₄ alkyl group, E is a carboxyl group, an alkali metal salt ofcarboxyl group, a chlorocarbonyl group, an acid anhydride, atrichloromethyl group, a trichloromethylcarbonyl group or an estergroup, Q is a hydrogen atom or an alkali metal atom, W is a hydrogenatom or any substituent, V is a hydrogen atom, an alkyl group or analkali metal atom, LG is a leaving group (e.g., chloro group, bromogroup, iodo group, methanesulfonate group etc.) or a hydroxyl group, andPG is an N-protecting group (e.g., benzyl group, tert-butoxycarbonylgroup, benzyloxycarbonyl group etc.).

Compound (V) can be produced by a condensation reaction of compound(III) and compound (IV).

Compound (III) can be produced according to a method known per se, forexample, the method described in Bioorganic and Medicinal Chemistry(Bioorg. Med. Chem.), 2001, vol. 9, page 1045-1057 and the like, or amethod analogous thereto.

Compound (IV) may be a commercially available product, or can beproduced according to a method known per se, for example, the methoddescribed in Bioorganic and Medicinal Chemistry Letters (Bioorg. Med.Chem. Lett.), 2005, vol. 15, page 833-838 or EP1757582 and the like, ora method analogous thereto.

When E is a carboxyl group, the condensation reaction is performedaccording to a conventional peptide synthesis technique, for example, anacid chloride method, an acid anhydride method, a mixed anhydridemethod, a method of using N,N′-dicyclohexylcarbodiimide (DCC), an activeester method, a method of using N,N′-carbonyldiimidazole (CDI), a methodof using diethyl cyanophosphate (DEPC), a method of usingN-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC.HCl)and 1-hydroxybenzotriazole (HOBt), or the like. Compound (IV) is used ina proportion of about 1 to 2 mol, preferably about 1.0 to 1.1 mol, per 1mol of compound (III). The reagent used in the above-mentioned method isused in a proportion of about 1 mol to large excess, preferably about1.1 to 5 mol, per 1 mol of compound (III). The reaction temperature isgenerally −10 to 80° C., preferably 0 to 30° C.

When E is an alkali metal salt of a carboxyl group, the condensationreaction is advantageously performed according to a method using WSC.HCland HOBt. Compound (IV) is used in an amount of about 1 to 2 mol,preferably about 1.0 to 1.1 mol, per 1 mol of compound (III). WSC.HCl isused in an amount of about 1 to 4 mol, preferably about 1.5 to 2.5 mol,per 1 mol of compound (III). HOBt is used in an amount of about 1 to 8mol, preferably about 2.5 to 5.0 mol, per 1 mol of compound (III). Thereaction temperature is generally −10 to 100° C., preferably 40 to 70°C.

In both cases, the condensation reaction is preferably performed in asolvent. Examples of the usable solvent include halogenated hydrocarbonssuch as dichloromethane, chloroform, carbon tetrachloride,1,2-dichloroethane and the like, ethers such as diethyl ether,tetrahydrofuran, dioxane and the like, amides such asN,N-dimethylformamide, N,N-dimethylacetamide and the like, dimethylsulfoxide, pyridine, acetonitrile and a mixed solvent thereof.

While the reaction time varies depending on the reagent or solvent to beused, it is generally 30 min to 3 days, preferably 30 min to 15 hr.

Compound (V) can also be produced by further carrying out theabove-mentioned reaction in combination with one or more of knownhydrolysis reaction, acylation reaction, alkylation reaction, aminationreaction, oxidation-reduction reaction, cyclization reaction, carbonchain extension reaction, substituent exchange reaction and the like, asdesired.

Compound (II) can be produced by removing the N-protecting group PG ofcompound (V). In addition, in each of the aforementioned reactions, whenthe starting compound has an amino group, a carboxyl group or a hydroxygroup as a substituent, a protecting group generally used in peptidechemistry and the like may be introduced into these groups. By removingthe protecting group as necessary after the reaction, the objectivecompound can be obtained. Introduction or removal of these protectivegroups may be carried out according to a method known per se, forexample, the method disclosed in Theodora W. Greene and Peter G. M.Wuts, “Protective Groups in Organic Synthesis, 3^(rd) Ed.”,Wiley-Interscience (1999), or the like.

Examples of the amino-protecting group include formyl group; C₁₋₆alkyl-carbonyl group, phenylcarbonyl group, C₁₋₆ alkoxy-carbonyl group,allyloxycarbonyl (Alloc) group, phenyloxycarbonyl group,fluorenylmethyloxycarbonyl (Fmoc) group, C₇₋₁₀ aralkyl-carbonyl group(e.g., benzylcarbonyl etc.), C₇₋₁₀ aralkyloxy-carbonyl group (e.g.,benzyloxycarbonyl (Cbz) etc.), C₇₋₁₀ aralkyl group (e.g., benzyl etc.),trityl group, phthaloyl group, dithiasuccinyl group,N,N-dimethylaminomethylene group, each of which optionally hassubstituent(s) and the like. Examples of the substituent include phenylgroup, halogen atom, C₁₋₆ alkyl-carbonyl group, C₁₋₆ alkoxy group (e.g.,methoxy, ethoxy, trifluoromethoxy etc.) optionally substituted byhalogen atom, nitro group and the like, and the number of thesubstituents is 1 to 3.

Examples of the protecting group for carboxyl group include C₁₋₆ alkylgroup, allyl group, benzyl group, phenyl group, trityl group,trialkylsilyl group, each of which optionally has substituent(s), andthe like. Examples of the substituent include halogen atom, a formylgroup, C₁₋₆ alkyl-carbonyl group, C₁₋₆ alkoxy group (e.g., methoxy,ethoxy, trifluoromethoxy etc.) optionally substituted by halogen atom,nitro group and the like, and the number of the substituents is 1 to 3.

Examples of the protecting group for hydroxy group include C₁₋₆ alkylgroup, C₇₋₂₀ aralkyl group (e.g., benzyl, trityl etc.), a formyl group,C₁₋₆ alkyl-carbonyl group, benzoyl group, C₇₋₁₀ aralkyl-carbonyl group(e.g., benzylcarbonyl etc.), 2-tetrahydropyranyl group,tetrahydrofuranyl group, trialkylsilyl group (e.g., trimethylsilyl,tert-butyldimethylsilyl, diisopropylethylsilyl etc.), each of whichoptionally has substituent(s), and the like. Examples of the substituentinclude halogen atom, C₁₋₆ alkyl group, phenyl group, C₇₋₁₀ aralkylgroup (e.g., benzyl etc.), C₁₋₆ alkoxy group, nitro group and the like,and the number of the substituents is 1 to 4.

When compound (II) is obtained as a free compound, it can be convertedto an object salt by a method known per se or a method analogousthereto, and when it is obtained as a salt, it can be converted to afree form or other object salt by a method known per se or a methodanalogous thereto.

Compound (VII) can be produced by a reaction of compound (VI) withcompound (IV).

Compound (VI) may be a commercially available product, or can beproduced according to a method known per se, for example, the methoddescribed in Journal of Organic Chemistry (J. Org. Chem.), 2002, vol.67, page 9276-9287 and the like, or a method analogous thereto.

The condensation reaction of compound (VI) and compound (IV) can beperformed under the conditions of the method used for the aforementionedproduction of compound (V).

Compound (V) can be produced from compound (VII).

The reaction from compound (VII) to compound (V) can be performedaccording to a method known per se, for example, the method described inBioorganic and Medicinal Chemistry Letters (Bioorg. Med. Chem. Lett.),2000, vol. 10, page 957-961 or Journal of Medicinal Chemistry (J. Med.Chem.), 1996, vol. 39, page 2856-2859 and the like, or a methodanalogous thereto.

Compound (V) can also be produced by further performing theabove-mentioned reaction in combination with one or more of knownhydrolysis, acylation reaction, alkylation reaction, amination reaction,oxidation reduction reaction, cyclization reaction, carbon chainextension reaction, substituent exchange reaction and the like, asdesired.

This method is used for the production of compound (II) wherein ring A¹is a fused imidazole ring.

Compound (VIII) can be produced from compound (IV).

Compound (VIII) can be produced using compound (IV) and according to aknown method, for example, the method described in Tetrahedron, 1993,vol. 49, page 4015-4034 and the like, or a method analogous thereto.

Compound (IX) may be a commercially available product, or can beproduced according to a method known per se, for example, the methoddescribed in Journal of Medicinal Chemistry (J. Med. Chem.), 1995, vol.38, page 4906-4916 or Journal of American Chemical Society (J. Am. Chem.Soc.), 2006, vol. 128, page 8569-8574 or Bioorganic and MedicinalChemistry (Bio. Med. Chem.), 1998, vol. 6, page 163-172 and the like ora method analogous thereto.

Compound (X) can be produced from compound (VIII) and compound (IX)according to a known method, for example, the method described inJournal of Chemical Society Perkin transaction 2 (J. Chem. Soc. PerkinTrans. 2), 2001, page 1817-1823 or Bioorganic and Medicinal ChemistryLetters (Bioorg. Med. Chem. Lett.), 2006, vol. 16, page 4638-4640, andthe like, or a method analogous thereto.

When LG is a substitutable leaving group, compound (XI) may be acommercially available product, or can be produced according to a methodknown per se, for example, the method described in WO2005003122 and thelike, or a method analogous thereto.

When LG is a hydroxyl group, compound (XI) may be a commerciallyavailable product, or can be produced according to a method known perse, for example, the method described in WO2005003122 and the like, or amethod analogous thereto.

Compound (XII) can be produced from compound (X) and compound (XI)according to a known method, for example, the method described inEP1479676 or Bioorganic and Medicinal Chemistry Letters (Bioorg. Med.Chem. Lett.), 2006, vol. 16, page 4638-4640 or Bioorganic and MedicinalChemistry Letters (Bioorg. Med. Chem. Lett.), 1997, vol. 7, page2819-2824, and the like, or a method analogous thereto.

Compound (XII) can also be produced by further performing theabove-mentioned reaction in combination with one or more of knownhydrolysis, acylation reaction, alkylation reaction, amination reaction,oxidation reduction reaction, cyclization reaction, carbon chainextension reaction, substituent exchange reaction and the like, asdesired.

Compound (II) can be produced by removing N-protecting group PG fromcompound (XII). In each of the above-mentioned reactions, when thestarting compound has an amino group, a carboxyl group or a hydroxylgroup as a substituent, these groups may be protected with a protectinggroup generally used in peptide chemistry and the like. In this case,the object compound can be obtained by removing the protecting group asnecessary after the reaction. These protecting groups can be introducedor removed according to a method known per se, for example, the methoddescribed in Theodora W. Greene and Peter G. M. Wuts, “Protective Groupsin Organic Synthesis, 3^(rd) Ed.”, Wiley-Interscience (1999) and thelike.

When compound (II) is obtained as a free compound, it can be convertedto an object salt by a method known per se or a method analogousthereto, and when it is obtained as a salt, it can be converted to afree form or other object salt by a method known per se or a methodanalogous thereto.

Compound (XII) can also be produced from compound (VIII) and compound(XIII).

Compound (XIII) may be a commercially available product, or can beproduced according to a method known per se, for example, the methoddescribed in Heterocycles (Heterocycles), 1998, vol. 48, page 1347-1364and the like, or a method analogous thereto.

The reaction to produce compound (XII) from compound (VIII) and compound(XIII) can be performed under the conditions employed for the productionof compound (X).

Compound (XII) can also be produced by further performing theabove-mentioned reaction in combination with one or more of knownhydrolysis, acylation reaction, alkylation reaction, amination reaction,oxidation reduction reaction, cyclization reaction, carbon chainextension reaction, substituent exchange reaction and the like, asdesired.

Compound (XIV) can be produced using compound (IX) and according to aknown method, for example, the method described in Journal of MedicinalChemistry (J. Med. Chem.), 2005, vol. 48, page 8289-8298 and the like ora method analogous thereto.

Compound (X) can be produced from compound (XIV) and compound (IV)according to a known method, for example, the method described inJournal of Medicinal Chemistry (J. Med. Chem.), 2005, vol. 48, page8289-8298 page and the like or a method analogous thereto.

Compound (X) can also be produced by performing the above-mentionedreaction in combination with one or more of known hydrolysis, acylationreaction, alkylation reaction, amination reaction, oxidation reductionreaction, cyclization reaction, carbon chain extension reaction,substituent exchange reaction and the like, as desired.

Compound (XV) can be produced using compound (XIII) and according to aknown method, for example, the method described in Journal of MedicinalChemistry (J. Med. Chem.), 2005, vol. 48, page 8289-8298 and the like ora method analogous thereto.

Compound (XII) can be produced from compound (XV) and compound (IV)according to a known method, for example, the method described inJournal of Medicinal Chemistry (J. Med. Chem.), 2005, vol. 48, page8289-8298 and the like or a method analogous thereto.

Compound (XII) can also be produced by further performing theabove-mentioned reaction in combination with one or more of knownhydrolysis, acylation reaction, alkylation reaction, amination reaction,oxidation reduction reaction, cyclization reaction, carbon chainextension reaction, substituent exchange reaction and the like, asdesired.

Compound (XV) may be a commercially available product, or can beproduced according to a method known per se, for example, the methoddescribed in Heterocycles (Heterocycles), 2006, vol. 67, page 769-775and the like, or a method analogous thereto.

Compound (X) can be produced from compound (XV) and compound (IV)according to a known method, for example, the method described inBioorganic and Medicinal Chemistry Letters (Bioorg. Med. Chem. Lett.),1997, vol. 7, page 1863-1868, and the like, or a method analogousthereto.

Compound (X) can also be produced by performing the above-mentionedreaction in combination with one or more of known hydrolysis, acylationreaction, alkylation reaction, amination reaction, oxidation reductionreaction, cyclization reaction, carbon chain extension reaction,substituent exchange reaction and the like, as desired.

Compound (XVI) may be a commercially available product, or can beproduced according to a method known per se, for example, the methoddescribed in Journal of Organic Chemistry (J. Org. Chem.), 2002, vol.69, page 2626-2629 and the like, or a method analogous thereto.

Compound (XVII) can be produced from compound (XVI) and compound (XI)according to a known method, for example, the method described inEP1479676 or Bioorganic and Medicinal Chemistry Letters (Bioorg. Med.Chem. Lett.), 2006, vol. 16, page 4638-4640 or Bioorganic and MedicinalChemistry Letters (Bioorg. Med. Chem. Lett.), 1997, vol. 7, page2819-2824, and the like or a method analogous thereto.

Compound (XVIII) can be produced by subjecting compound (XVII) to knownhydrolysis, for example, alkali hydrolysis or acid hydrolysis.

Compound (XII) can be produced from compound (XVIII) and compound (IV)according to a known method, for example, the method described inBioorganic and Medicinal Chemistry Letters (Bioorg. Med. Chem. Lett.),1997, vol. 7, page 1863-1868, and the like or a method analogousthereto.

Compound (XII) can also be produced by further performing theabove-mentioned reaction in combination with one or more of knownhydrolysis, acylation reaction, alkylation reaction, amination reaction,oxidation reduction reaction, cyclization reaction, carbon chainextension reaction, substituent exchange reaction and the like, asdesired.

This method is used for the production of a compound wherein compound(IV) is a structure shown by compound (XXIV).

Compound (XIX) can be produced according to a method known per se, forexample, U.S. Pat. No. 6,018,046 etc. or a method analogous thereto.

Compounds (XX), (XXI) and (XXII) can be each produced by subjectingcompound (XIX) to a known reduction reaction, for example, ahydrogenation reaction in the presence of a metal catalyst and the like,and then introducing a PG group (a protecting group) by known reactions.

The hydrogenation reaction and the subsequent introduction of theprotecting group (PG group) can be performed according to a knownmethod, for example, the method described in Tetrahedron Letters(Tetrahedron Lett.), 1994, vol. 35, page 4515-4518 or Tetrahedron:Asymmetry (Tetrahedron: Asymmetry.), 2003, vol. 14, page 1541-1545 orTetrahedron Letters (Tetrahedron Lett.), 2003, vol. 44, page 1611-1614and the like, or a method analogous thereto.

The hydrogenation reaction is more advantageously performed under acidicconditions. Preferable examples of the acid for this step includemineral acids such as mineral acid, hydrochloric acid and the like,organic acids such as acetic acid and the like, and the like. The amountof the acid to be used is about 1 mol to large excess per 1 mol ofcompound (XIX).

As the metal catalyst used for the hydrogenation reaction, for example,rhodium carbon, platinum oxide, palladium carbon, rhodium-platinum oxidealloy and the like are preferable. The amount of the catalyst to be usedis about 0.01 g to 1 g, preferably about 0.05 g to 0.3 g, per 1 g ofcompound (XIX).

The hydrogenation reaction is advantageously performed using a solventinert to the reaction. The solvent is not particularly limited as longas the reaction proceeds, for example, organic acid such as acetic acidand the like, mineral acid such as hydrochloric acid and the like,alcohols such as methanol, ethanol, propanol and the like, hydrocarbonssuch as benzene, toluene, cyclohexane, hexane and the like, ethers suchas diethyl ether, tetrahydrofuran, dioxane and the like, esters such asethyl acetate and the like, highly-polar solvent such asN,N-dimethylformamide or N-methylpyrrolidone and the like or a mixedsolvent thereof and the like are preferable.

While the reaction time varies depending on the reagents and solvents tobe used, it is generally 30 min to 60 hr, preferably 30 min to 30 hr.

The reaction temperature is generally 0 to 150° C., preferably 20 to 70°C.

After the reduction reaction, the reaction mixture is neutralized byadding an inorganic base (e.g., sodium hydroxide, potassium carbonateetc.), an organic base (e.g., triethylamine etc.) and the like andconcentrated or, the reaction mixture is directly concentrated and theconcentrate is neutralized by adding an inorganic base (e.g., sodiumhydroxide, potassium carbonate etc.), an organic base (e.g.,triethylamine etc.) and the like, and the protecting group (PG group) isintroduced thereinto to give compounds (XX), (XXI) and (XXII). Theprotecting group (PG group) can be introduced according to a methodknown per se, for example, the method described in Theodora W. Greeneand Peter G. M. Wuts, “Protective Groups in Organic Synthesis, 3^(rd)Ed.”, Wiley-Interscience (1999), and the like.

Compounds (XX), (XXI) and (XXII) can be isolated from the mixture ofcompounds (XX), (XXI) and (XXII), respectively, by a known purificationmethod, for example, silica gel column chromatography,recrystallization, high-pressure liquid chromatography and the like.

Compound (XXI) can also be produced according to a method known per se,for example, the method described in WO97/18813 and the like, or amethod analogous thereto.

Compound (XXIII) can be produced by a rearrangement reaction (e.g.,Curtius rearrangement and the like) of compound (XXI) or compound(XXII).

Compound (XXIII) can be produced according to a method known per se, forexample, the method described in U.S. Pat. No. 5,817,678 and the like,or a method analogous thereto.

Compound (XXIV) can be produced by a reaction to introduce substituentR¹ into the amino group of compound (XXIII) (e.g., reductivealkylation).

Compound (XXIV) can be produced according to a known method, forexample, Bioorganic and Medicinal Chemistry Letters (Bioorg. Med. Chem.Lett.), 2005, vol. 15, page 833-838 or a method analogous thereto.

This method is used for the production of a compound wherein compound(IV) is a structure shown by compound (XXVIII).

Compound (XXV) can be separated from compound (XXI), which is a mixtureof compounds (XXV) and (XXVI), by a known purification method, forexample, diastereomer salt method, optically active columnchromatography and the like.

Compound (XXV) can also be produced according to a method known per se,for example, the method described in Tetrahedron Letters, 2003, vol. 44,page 1611-1614 and the like, or a method analogous thereto.

Compound (XXVII) can be produced by a rearrangement reaction (e.g.,Curtius rearrangement and the like) of compound (XXV).

Compound (XXVII) can be produced according to a known method, forexample, the method described in Tetrahedron Letters, 2003, vol. 44,page 1611-1614 and the like, or a method analogous thereto.

Compound (XXVIII) can be produced by a reaction to introduce substituentR¹ into the amino group of compound (XXVII) (e.g., reductivealkylation).

Compound (XXVIII) can be produced according to a known method, forexample, Bioorganic and Medicinal Chemistry Letters (Bioorg. Med. Chem.Lett.), 2005, vol. 15, page 833-838 or a method analogous thereto.

Compound (XXIX) can also be produced according to a method known per se,for example, the method described in Tetrahedron Letters, 2003, vol. 44,page 1611-1614 and the like, or a method analogous thereto.

Compound (XXV) can be produced by a known asymmetric esterificationreaction and using compound (XXIX).

Compound (XXV) can also be produced according to a known method, forexample, the method described in Journal of American Chemical Society(J. Am. Chem. Soc.), 2000, vol. 122, page 9542-9543 and the like or amethod analogous thereto.

Compound (XXXI) can be produced by a condensation reaction of compound(XXIX) and compound (XXX).

Compound (XXIX) can be produced according to a method known per se, forexample, the method described in Bioorganic and Medicinal Chemistry(Bioorg. Med. Chem.), 2001, vol. 9, page 1045-1057 and the like orJournal of Medicinal Chemistry (J. Med. Chem.), 1995, vol. 38, page86-97 or Organic and Biomolecular Chemistry, 2003, vol. 1, page2103-2110 or Chemistry of Heterocyclic Compounds (Chemistry ofHeterocyclic Compounds), 1982, vol. 18, page 758-761 or WO2007094513 orEP1867331, or a method analogous thereto.

Compound (XXX) may be a commercially available product, or can beproduced according to a method known per se, for example, the methoddescribed in Bioorganic and Medicinal Chemistry Letters (Bioorg. Med.Chem. Lett.), 2005, vol. 15, page 833-838 or EP1757582 and the like, themethod described for the synthesis of compound (XXVIII), or a methodanalogous thereto.

When E is a carboxyl group, the condensation reaction is performed by ageneral method of peptide synthesis, for example, acid chloride method,acid anhydride method, mixed acid anhydride method, a method usingN,N′-dicyclohexylcarbodiimide (DCC), activity ester method, a methodusing N,N′-carbonyldiimidazole (CDI), a method using diethylcyanophosphate (DEPC), a method usingN-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC.HCl)and 1-hydroxybenzotriazole (HOBt) and the like. Compound (XXX) is usedin a proportion of about 1 to 2 mol, preferably about 1.0 to 1.1 mol,per 1 mol of compound (XXIX). The reagent used in the above-mentionedmethod is used in a proportion of about 1 mol to large excess,preferably about 1.1 to 5 mol, per 1 mol of compound (XXIX). Thereaction temperature is generally −10 to 80° C., preferably 0 to 30° C.

When E is an alkali metal salt of a carboxyl group, the condensationreaction is advantageously performed by a method using WSC.HCl and HOBt.Compound (XXX) is used in a proportion of about 1 to 2 mol, preferablyabout 1.0 to 1.1 mol, per 1 mol of compound (XXIX). WSC.HCl is used in aproportion of about 1 to 4 mol, preferably about 1.5 to 2.5 mol, per 1mol of compound (XXIX). HOBt is used in a proportion of about 1 to 8mol, preferably about 2.5 to 5.0 mol, per 1 mol of compound (XXIX). Thereaction temperature is generally −10 to 100° C., preferably 40 to 70°C.

In any case, the condensation reaction is preferably performed in asolvent, and examples of the solvent include halogenated hydrocarbonssuch as dichloromethane, chloroform, carbon tetrachloride,1,2-dichloroethane and the like, ethers such as diethyl ether,tetrahydrofuran, dioxane and the like, amides such asN,N-dimethylformamide, N,N-dimethylacetamide and the like, dimethylsulfoxide, pyridine, acetonitrile and a mixed solvent thereof.

While the reaction time varies depending on the reagents and solvents tobe used, it is generally 30 min to 3 days, preferably 30 min to 15 hr.

Compound (XXXI) can also be produced by further performing theabove-mentioned reaction in combination with one or more of knownhydrolysis, acylation reaction, alkylation reaction, amination reaction,oxidation reduction reaction, cyclization reaction, carbon chainextension reaction, substituent exchange reaction and the like, asdesired.

Compound (I) can be produced by removing N-protecting group PG fromcompound (XXXI). In each of the above-mentioned reactions, when thestarting compound has an amino group, a carboxyl group or a hydroxylgroup as a substituent, these groups may be protected with a protectinggroup generally used in peptide chemistry and the like. In this case,the object compound can be obtained by removing the protecting group asnecessary after the reaction. These protecting groups can be introducedor removed according to a method known per se, for example, the methoddescribed in Theodora W. Greene and Peter G. M. Wuts, “Protective Groupsin Organic Synthesis, 3^(rd) Ed.”, Wiley-Interscience (1999) and thelike, or a method analogous thereto.

As the amino-protecting group, for example, a formyl group; C₁₋₆alkyl-carbonyl group, phenylcarbonyl group, C₁₋₆ alkoxy-carbonyl group,allyloxycarbonyl (Alloc) group, phenyloxycarbonyl group,fluorenylmethyloxycarbonyl (Fmoc) group, C₇₋₁₀ aralkyl-carbonyl group(e.g., benzylcarbonyl and the like), C₇₋₁₀ aralkyloxy-carbonyl group(e.g., benzyloxycarbonyl (Cbz) and the like), C₇₋₁₀ aralkyl group (e.g.,benzyl and the like), trityl group, phthaloyl group, dithiasuccinoylgroup, N,N-dimethylaminomethylene group, each optionally havingsubstituent(s), and the like can be mentioned. As the substituent(s),for example, phenyl group, a halogen atom, C₁₋₆ alkyl-carbonyl group,C₁₋₆ alkoxy group optionally substituted by halogen atom(s) (e.g.,methoxy, ethoxy, trifluoromethoxy and the like), nitro group and thelike can be used. The number of the substituents is 1 to 3.

As the carboxyl-protecting group, for example, C₁₋₆ alkyl group, allylgroup, benzyl group, phenyl group, trityl group, trialkylsilyl group,each optionally having substituent(s), and the like can be mentioned. Asthe substituent(s), for example, a halogen atom, a formyl group, C₁₋₆alkyl-carbonyl group, C₁₋₆ alkoxy group optionally substituted byhalogen atom(s) (e.g., methoxy, ethoxy, trifluoromethoxy and the like),nitro group and the like can be used. The number of the substituents is1 to 3.

As the hydroxy-protecting group, for example, C₁₋₆ alkyl group, C₇₋₂₀aralkyl group (e.g., benzyl, trityl and the like), a formyl group, C₁₋₆alkyl-carbonyl group, benzoyl group, C₇₋₁₀ aralkyl-carbonyl group (e.g.,benzylcarbonyl and the like), 2-tetrahydropyranyl group,tetrahydrofuranyl group, trialkylsilyl group (e.g., trimethylsilyl,tert-butyldimethylsilyl, diisopropylethylsilyl and the like), eachoptionally having substituent(s), and the like can be mentioned. As thesubstituent(s), for example, a halogen atom, C₁₋₆ alkyl group, phenylgroup, C₇₋₁₀ aralkyl group (e.g., benzyl and the like), C₁₋₆ alkoxygroup, nitro group and the like can be used. The number of thesubstituents is 1 to 4.

When compound (I) is obtained as a free compound, it can be converted tothe object salt according to a method known per se or a method analogousthereto, and when it is obtained as a salt, it can be converted to afree compound or other object salt according to a method known per se ora method analogous thereto.

Compound (XXXII) can be produced by reacting compound (VI) with compound(XXX).

Compound (VI) may be a commercially available product, or can beproduced according to a method known per se, for example, the methoddescribed in Journal of Organic Chemistry (J. Org. Chem.), 2002, vol.67, page 9276-9287 and the like, or a method analogous thereto.

The condensation reaction of compound (VI) and compound (XXX) can beperformed under the conditions employed for the production of theaforementioned compound (V).

Compound (XXXI) can be produced from compound (XXXII).

The reaction from compound (XXXII) to compound (XXXI) can be performedaccording to a method known per se, for example, the method described inBioorganic and Medicinal Chemistry Letters (Bioorg. Med. Chem. Lett.),2000, vol. 10, page 957-961 or Journal of Medicinal Chemistry (J. Med.Chem.), 1996, vol. 39, page 2856-2859 and the like or a method analogousthereto.

Compound (XXXI) can also be produced by performing the above-mentionedreaction in combination with one or more of known hydrolysis, acylationreaction, alkylation reaction, amination reaction, oxidation reductionreaction, cyclization reaction, carbon chain extension reaction,substituent exchange reaction and the like, as desired.

This method can be used for the production of compound (I) wherein ringA is a fused imidazole ring.

Compound (XXXIII) can be produced from compound (XXX).

Compound (XXXIII) can be produced using compound (XXX) and according toa known method, for example, the method described in Tetrahedron(Tetrahedron), 1993, vol. 49, page 4015-4034 and the like or a methodanalogous thereto.

Compound (IX) may be a commercially available product, or can beproduced according to a method known per se, for example, the methoddescribed in Journal of Organic Chemistry (J. Org. Chem.), 1995, vol.38, page 4906-4916 or Journal of American Chemical Society (J. Am. Chem.Soc.), 2006, vol. 128, page 8569-8574, or Bioorganic and MedicinalChemistry (Bio. Med. Chem.), 1998, vol. 6, page 163-172 and the like, ora method analogous thereto.

Compound (XXXIV) can be produced from compound (XXXIII) and compound(IX) according to a known method, for example, the method described inJournal of Chemical Society Perkin transaction 2 (J. Chem. Soc. PerkinTrans. 2), 2001, page 1817-1823 or Bioorganic and Medicinal ChemistryLetters (Bioorg. Med. Chem. Lett.), 2006, vol. 16, page 4638-4640, andthe like or a method analogous thereto.

Compound (XXXIV) can also be produced by further performing theabove-mentioned reaction in combination with one or more of knownhydrolysis, acylation reaction, alkylation reaction, amination reaction,oxidation reduction reaction, cyclization reaction, carbon chainextension reaction, substituent exchange reaction and the like, asdesired.

When LG is a substitutable leaving group, compound (XXXV) may be acommercially available product, or can be produced according to a methodknown per se, for example, the method described in WO2005003122 and thelike, or a method analogous thereto.

When LG is a hydroxyl group, compound (XXXV) may be a commerciallyavailable product, or can be produced according to a method known perse, for example, the method described in WO2005003122 and the like, or amethod analogous thereto.

Compound (XXXVI) can be produced from compound (XXXIV) and compound(XXXV) according to a known method, for example, the method described inEP1479676 or Bioorganic and Medicinal Chemistry Letters (Bioorg. Med.Chem. Lett.), 2006, vol. 16, page 4638-4640 or Bioorganic and MedicinalChemistry Letters (Bioorg. Med. Chem. Lett.), 1997, vol. 7, page2819-2824, and the like or a method analogous thereto.

Compound (XXXVI) can also be produced by further performing theabove-mentioned reaction in combination with one or more of knownhydrolysis, acylation reaction, alkylation reaction, amination reaction,oxidation reduction reaction, cyclization reaction, carbon chainextension reaction, substituent exchange reaction and the like, asdesired.

Compound (I) can be produced by removing N-protecting group PG fromcompound (XXXVI). In each of the above-mentioned reactions, when thestarting compound has an amino group, a carboxyl group or a hydroxylgroup as a substituent, these groups may be protected with a protectinggroup generally used in peptide chemistry and the like. In this case,the object compound can be obtained by removing the protecting group asnecessary after the reaction. These protecting groups can be introducedor removed according to a method known per se, for example, a methodanalogous to the method described in Theodora W. Greene and Peter G. M.Wuts, “Protective Groups in Organic Synthesis, 3^(rd) Ed.”,Wiley-Interscience (1999) and the like.

When X of compound (I) is a hydrogen atom, the compound can be producedby removing N-protecting group PG from compound (XXXIV). In each of theabove-mentioned reactions, when the starting compound has an aminogroup, a carboxyl group or a hydroxyl group as a substituent, thesegroups may be protected with a protecting group generally used inpeptide chemistry and the like. In this case, the object compound can beobtained by removing the protecting group as necessary after thereaction. These protecting groups can be introduced or removed accordingto a method known per se, for example, a method analogous to the methoddescribed in Theodora W. Greene and Peter G. M. Wuts, “Protective Groupsin Organic Synthesis, 3^(rd) Ed.”, Wiley-Interscience (1999) and thelike.

When compound (I) is obtained as a free compound, it can be converted toan object salt by a method known per se or a method analogous thereto,and when it is obtained as a salt, it can be converted to a free form orother object salt by a method known per se or a method analogousthereto.

Compound (XXXVI) can also be produced from compound (XXXIII) andcompound (XXXVII).

Compound (XXXVII) may be a commercially available product, or can beproduced according to a method known per se, for example, the methoddescribed in Heterocycles (Heterocycles), 1998, vol. 48, page 1347-1364and the like, or a method analogous thereto.

The reaction to produce compound (XXXVI) from compound (XXXIII) andcompound (XXXVII) can be performed under the conditions employed for theproduction of compound (XXXIV).

Compound (XXXVI) can also be produced by further performing theabove-mentioned reaction in combination with one or more of knownhydrolysis, acylation reaction, alkylation reaction, amination reaction,oxidation reduction reaction, cyclization reaction, carbon chainextension reaction, substituent exchange reaction and the like, asdesired.

Compound (XXXIV) can be produced from compound (XIV) and compound (XXX)according to a known method, for example, the method described inJournal of Medicinal Chemistry (J. Med. Chem.), 2005, vol. 48, page8289-8298 and the like or a method analogous thereto.

Compound (XXXIV) can also be produced by further performing theabove-mentioned reaction in combination with one or more of knownhydrolysis, acylation reaction, alkylation reaction, amination reaction,oxidation reduction reaction, cyclization reaction, carbon chainextension reaction, substituent exchange reaction and the like, asdesired.

Compound (XXXIX) can be produced using compound (XXXVIII) and accordingto a known method, for example, the method described in Journal ofMedicinal Chemistry (J. Med. Chem.), 2005, vol. 48, page 8289-8298 andthe like or a method analogous thereto.

Compound (XXXVI) can be produced from compound (XXXIX) and compound(XXX) according to a known method, for example, the method described inJournal of Medicinal Chemistry (J. Med. Chem.), 2005, vol. 48, page8289-8298 and the like or a method analogous thereto.

Compound (XXXVI) can also be produced by further performing theabove-mentioned reaction in combination with one or more of knownhydrolysis, acylation reaction, alkylation reaction, amination reaction,oxidation reduction reaction, cyclization reaction, carbon chainextension reaction, substituent exchange reaction and the like, asdesired.

Compound (XV) may be a commercially available product, or can beproduced according to a method known per se, for example, the methoddescribed in Heterocycles, 2006, vol. 67, page 769-775 and the like, ora method analogous thereto.

Compound (XXXIV) can be produced from compound (XV) and compound (XXX)according to a known method, for example, the method described inBioorganic and Medicinal Chemistry Letters (Bioorg. Med. Chem. Lett.),1997, vol. 7, page 1863-1868, and the like or a method analogousthereto.

Compound (XXXIV) can also be produced by further performing theabove-mentioned reaction in combination with one or more of knownhydrolysis, acylation reaction, alkylation reaction, amination reaction,oxidation reduction reaction, cyclization reaction, carbon chainextension reaction, substituent exchange reaction and the like, asdesired.

Compound (XVI) may be a commercially available product, or can beproduced according to a method known per se, for example, the methoddescribed in Journal of Organic Chemistry (J. Org. Chem.), 2004, vol.69, page 2626-2629 and the like, or a method analogous thereto.

Compound (XXXX) can be produced from compound (XVI) and compound (XXXV)according to a known method, for example, the method described inEP1479676 or Bioorganic and Medicinal Chemistry Letters (Bioorg. Med.Chem. Lett.), 2006, vol. 16, page 4638-4640 or Bioorganic and MedicinalChemistry Letters (Bioorg. Med. Chem. Lett.), 1997, vol. 7, page2819-2824, and the like or a method analogous thereto.

Compound (XXXXI) can be produced by a known hydrolysis, for example,alkali hydrolysis or acid hydrolysis.

Compound (XXXVI) can be produced from compound (XXXXI) and compound(XXX) according to a known method, for example, the method described inBioorganic and Medicinal Chemistry Letters (Bioorg. Med. Chem. Lett.),1997, vol. 7, page 1863-1868, and the like or a method analogousthereto.

Compound (XXXVI) can also be produced by further performing theabove-mentioned reaction in combination with one or more of knownhydrolysis, acylation reaction, alkylation reaction, amination reaction,oxidation reduction reaction, cyclization reaction, carbon chainextension reaction, substituent exchange reaction and the like, asdesired.

Compound (I) and compound (II) may be used as prodrugs. A prodrug ofcompound (I) or compound (II) means a compound which is converted tocompound (I) or compound (II) with a reaction due to an enzyme, angastric acid, etc. under the physiological condition in the living body,that is a compound which is converted to compound (I) or compound (II)with oxidation, reduction, hydrolysis, etc. according to an enzyme; acompound which is converted to compound (I) or compound (II) byhydrolysis etc. due to gastric acid, etc.

Examples of a prodrug of compound (I) or compound (II) include acompound wherein an amino group of compound (I) or compound (II) isacylated, alkylated or phosphorylated (e.g., compound wherein aminogroup of compound (I) or compound (II) is eicosanoylated, alanylated,pentylaminocarbonylated,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated,tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated ortert-butylated, and the like); a compound wherein a hydroxy group ofcompound (I) or compound (II) is acylated, alkylated, phosphorylated orborated (e.g., a compound wherein a hydroxy group of compound (I) orcompound (II) is acetylated, palmitoylated, propanoylated, pivaloylated,succinylated, fumarylated, alanylated ordimethylaminomethylcarbonylated, and the like); a compound wherein acarboxyl group of compound (I) or compound (II) is esterified oramidated (e.g., a compound wherein a carboxyl group of compound (I) orcompound (II) is ethyl esterified, phenyl esterified, carboxymethylesterified, dimethylaminomethyl esterified, pivaloyloxymethylesterified, ethoxycarbonyloxyethyl esterified, phthalidyl esterified,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterified,cyclohexyloxycarbonylethyl esterified or methylamidated, and the like)and the like. These compounds can be produced from compound (I) by amethod known per se.

A prodrug of compound (I) and compound (II) may also be one which isconverted into compound (I) or compound (II) under a physiologicalcondition, such as those described in IYAKUHIN no KAIHATSU (Developmentof Pharmaceuticals), Vol. 7, Design of Molecules, p. 163-198, Publishedby HIROKAWA SHOTEN (1990).

When compound (I) and compound (II) has an isomer such as opticalisomer, stereoisomer, positional isomer, rotational isomer and the like,any isomers and a mixture thereof are encompassed in compound (I) orcompound (II). For example, when compound (I) or compound (II) has anoptical isomer, an optical isomer resolved from a racemate is alsoencompassed in compound (I) and compound (II). Such isomer can beobtained as a single product by a synthesis method, a separation method(e.g., concentration, solvent extraction, column chromatography,recrystallization etc.), optical resolution method (e.g., fractionalrecrystallization, chiral column method, diastereomer method etc.) andthe like known per se.

Compound (I) and compound (II) may be a crystal, and both a singlecrystal and crystal mixtures are encompassed in compound (I) andcompound (II). Crystals can be produced by crystallization according tocrystallization methods known per se.

Compound (I) and compound (II) may be a solvate (e.g., hydrate etc.) ora non-solvate (e.g., non-hydrate etc.), both of which are encompassed incompound (I) and compound (II). A compound labeled with an isotope(e.g., ³H, ¹⁴C, ³⁵S, ¹²⁵I and the like) and the like is also encompassedin compound (I) and compound (II).

Deuterium-converted compound wherein ¹H has been converted to ²H(D) arealso encompassed in the compound (I) and compound (II).

Compound (I) or compound (II) or its prodrug, or salts thereof(hereinafter, sometimes to be abbreviated to as a compound of thepresent invention) exhibit superior renin inhibitory activity. They havelow toxicity (e.g., acute toxicity, chronic toxicity, genetic toxicity,reproductive toxicity, cardiac toxicity, drug interaction,carcinogenicity, etc.) and high water-solubility, and are excellent inthe aspects of stability, pharmacokinetics (absorbability, distribution,metabolism, excretion, etc.) and efficacy, thus being useful asmedicine.

The compound of the present invention acts as a renin inhibitory drug inmammals (e.g., mouse, rat, hamster, rabbit, cat, dog, cattle, sheep,monkey, human, etc.), and is useful as a drug inhibiting the RA systemby inhibiting the biosynthesis of AII, and is useful as an agent for theprophylaxis or treatment of various diseases caused by the RA system.

Examples of such diseases include hypertension (e.g., essentialhypertension, renal vascular hypertension, renoparenchymal hypertension,primary aldosteronism, Cushing's syndrome etc.), blood pressurecircadian rhythm abnormality, heart diseases (e.g., cardiac hypertrophy,acute heart failure, chronic heart failure including congestive heartfailure, failure of expansion, cardiac myopathy, angina pectoris,myocarditis, atrial fibrillation, arrhythmia, tachycardia, cardiacinfraction etc.), cerebrovascular disorders (e.g., asymptomaticcerebrovascular disorder, transient cerebral ischemia, cerebrovasculardementia, hypertensive encephalopathy, cerebral infarction etc.),cerebral edema, cerebral circulatory disorder, recurrence and sequela ofcerebrovascular disorders (e.g., neurotic symptom, psychic symptom,subjective symptom, disorder in daily living activities etc.), ischemicperipheral circulation disorder, myocardial ischemia, venousinsufficiency, progression of cardiac insufficiency after myocardialinfarction, renal diseases (e.g., nephritis, glomerulonephritis,glomerulosclerosis, renal failure, nephrotic syndrome, thromboticvasculopathy, complication of dialysis, organ damage includingnephropathy by radiation irradiation etc.), arteriosclerosis includingatherosclerosis (e.g., aneurysm, coronary arteriosclerosis, cerebralarteriosclerosis, peripheral arteriosclerosis etc.), vascularhypertrophy, vascular hypertrophy or obliteration and organ damagesafter intervention (e.g., percutaneous transluminal coronaryangioplasty, stenting, coronary angioscopy, intravascular ultrasound,dounce thrombolytic therapy etc.), vascular re-obliteration andrestenosis after bypass, polycythemia, hypertension, organ damage andvascular hypertrophy after transplantation, rejection aftertransplantation, ocular diseases (e.g., glaucoma, ocular hypertensionetc.), thrombosis, multiple organ disorder, endothelial dysfunction,hypertensive tinnitus, other cardiovascular diseases (e.g., deep veinthrombosis, obstructive peripheral circulatory disorder,arteriosclerosis obliterans, thromboangiitis obliterans, ischemiccerebral circulatory disorder, Raynaud's disease, Berger disease etc.),metabolic and/or nutritional disorders (e.g., diabetes, impaired glucosetolerance, insulin resistance, hyperinsulinemia, diabetic nephropathy,diabetic retinopathy, diabetic neuropathy, obesity, hyperlipidemia,hypercholesterolemia, hyperuricacidemia, hyperkalemia, hypernatremiaetc.), metabolic syndrome, nonalcoholic steatohepatitis (NASH),nonalcoholic fatty liver disease (NAFLD), nerve degeneration diseases(e.g., Alzheimer's disease, Parkinson's disease, Creutzfeldt-Jakobdisease, multiple sclerosis, amyotrophic lateral sclerosis, AIDSencephalopathy etc.), central nervous system disorders (e.g., damagessuch as cerebral hemorrhage and cerebral infarction, and sequela andcomplication thereof, head injury, spinal injury, cerebral edema,sensory malfunction, sensory functional disorder, autonomic nervoussystem disorder, autonomic nervous system malfunction etc.), dementia,migraine, defects of memory, disorder of consciousness, amnesia, anxietysymptom, catatonic symptom, discomfort mental state, sleep disorder,agrypnia, sychopathies (e.g., depression, epilepsy, alcoholism etc.),inflammatory diseases (e.g., arthritis such as rheumatoid arthritis,osteoarthritis, rheumatoid myelitis, periostitis etc.; inflammationafter operation or injury; remission of swelling; pharyngitis; cystitis;pneumonia; atopic dermatitis; inflammatory intestinal diseases such asCrohn's disease, ulcerative colitis etc.; meningitis; inflammatoryocular disease; inflammatory pulmonary disease such as pneumonia,pulmonary silicosis, pulmonary sarcoidosis, pulmonary tuberculosisetc.), allergic diseases (e.g., allergic rhinitis, conjunctivitis,gastrointestinal allergy, pollinosis, anaphylaxis etc.), chronicobstructive pulmonary disease, interstitial pneumonia, pneumocytiscarinni pneumonia, collagen diseases (e.g., systemic lupuserythematodes, scleroderma, polyarteritis etc.), hepatic diseases (e.g.,hepatitis including chronic hepatitis, hepatic cirrhosis etc.), portalhypertension, digestive system disorders (e.g., gastritis, gastriculcer, gastric cancer, gastric disorder after operation, dyspepsia,esophageal ulcer, pancreatitis, colon polyp, cholelithiasis,hemorrhoidal disease, varices ruptures of esophagus and stomach etc.),blood and/or myelopoietic diseases (e.g., erythrocytosis, vascularpurpura, autoimmune hemolytic anemia, disseminated intravascularcoagulation syndrome, multiple myelopathy etc.), bone diseases (e.g.,fracture, refracture, osteoporosis, osteomalacia, bone Paget's disease,sclerosing myelitis, rheumatoid arthritis, joint tissue dysfunction andthe like caused by osteoarthritis of the knee and diseases similar tothese), solid tumor, tumors (e.g., malignant melanoma, malignantlymphoma, cancer of digestive organs (e.g., stomach, intestine etc.)etc.), cancer and cachexia following cancer, metastasis cancer,endocrinopathy (e.g., Addison's disease, pheochromocytoma etc.), urinaryorgan and/or male genital diseases (e.g., cystitis, prostatichypertrophy, prostatic cancer, sex infectious disease etc.), femaledisorders (e.g., climacteric disorder, gestosis, endometriosis,hysteromyoma, ovarian disease, breast disease, sex infectious diseaseetc.), disease relating to environment and occupational factors (e.g.,radiation hazard, hazard by ultraviolet, infrared or laser beam,altitude sickness etc.), respiratory diseases (e.g., cold syndrome,pneumonia, asthma, pulmonary hypertension, pulmonary thrombosis andpulmonary embolism etc.), infectious diseases (e.g., viral infectiousdiseases with cytomegalovirus, influenza virus, herpes virus etc.,rickettsiosis, bacterial infectious disease etc.), toxemias (e.g.,sepsis, septic shock, endotoxin shock, Gram-negative sepsis, toxic shocksyndrome etc.), otorhinolaryngological diseases (e.g., Meniere'ssyndrome, tinnitus, dysgeusia, vertigo, disequilibrium, dysphagia etc.),skin diseases (e.g., keloid, Hemangioma, psoriasis etc.), eye disease(e.g., cataract, glaucoma etc.), intradialytic hypotension, myastheniagravis, systemic diseases such as chronic fatigue syndrome and the like.

The compound of the present invention can be used in combination with anexisting hypertension therapeutic drug such as an ACE inhibitor(captopril, enalapril maleate, alacepril, delapril hydrochloride,imidapril hydrochloride, quinapril hydrochloride, cilazapril, temocaprilhydrochloride, trandolapril, benazepril hydrochloride, perindopril,lisinopril, etc.), ARB (losartan potassium, candesartan cilexetil,valsartan, TAK-536, TAK-491, TAK-591, irbesartan, telmisartan,eprosartan, olmesartan medoxomil, etc.), an aldosterone receptorantagonist (spironolactone, eplerenone, etc.), a Ca-ion channelinhibitor (verapamil hydrochloride, diltiazem hydrochloride, nifedipine,amlodipine besilate, azelnidipine, aranidipine, efonidipinehydrochloride, cilnidipine, nicardipine hydrochloride, nisoldipine,nitrendipine, nilvadipine, barnidipine hydrochloride, felodipine,benidipine hydrochloride, manidipine hydrochloride, etc.), diuretic(trichlormethiazide, hydrochlorothiazide, benzylhydrochlorothiazide,indapamide, tripamide, meticrane, mefruside, furosemide, triamterene,chlorthalidon etc.), a β-blocker (propranolol hydrochloride, atenolol,metoprolol tartrate, bisoprolol fumarate, etc.), an α,β-blocker(carvedilol, etc.), and the like.

Moreover, the compound of the present invention can be also used incombination with an antithrombotic drug such as heparin sodium, heparincalcium, warfarin calcium (Warfarin), a blood coagulation factor Xainhibitor, drug having a function of balance correction in thecoagulation-fibrinolysis system, an oral thrombin inhibitor(aragatroban, dabigatran, etc.), a thrombolytic drug (tPA, urokinase,etc.), an antiplatelet drug [aspirin, sulfinpyrazone (Anturane),dipyridamol (Persantine), ticlopidine hydrochloride (Panaldine),clopidogrel, cilostazol (Pletal), GPIIb/IIIa antagonist (abciximab,tirofiban, etc.)], and the like. Also, the compound can be used incombination with a lipid lowering drug or a cholesterol lowering drug.Examples thereof include a squalene synthase inhibitor (lapaquistatacetate etc.), fibrates (clofibrate, benzafibrate, gemfibrozil, etc.),nicotinic acid, its derivatives and analogs (acipimox, probucol, etc.),a bile acid binding resin (cholestyramine, colestipol, etc.), an omega-3polyunsaturated fatty acid (EPA (eicosapentaenoic acid), DHA(docosahexaenoic acid), or a mixture thereof etc.), a compoundinhibiting cholesterol absorption (sitosterol, neomycin, etc.), and asqualene epoxidase inhibitor (NB-598 and its analogs, etc.).Furthermore, other possible combination components are anoxidosqualene-lanosterol cyclase, for example, a decalin derivative, anazadecalin derivative, an indane derivative and the like. Combinationwith a HMG-CoA reductase (3-hydroxy-3-methylglutaryl coenzyme Areductase) inhibitor (atorvastatin calcium hydrate, pravastatin sodium,simvastatin, itavastatin, lovastatin, fluvastatin, etc.) is alsopossible.

The compound of the present invention can also be used in combinationwith a therapeutic drug for diabetes or a therapeutic drug for diabeticcomplications. For example, the compound of the present invention can beused in combination with an insulin preparation, an insulin sensitivityimproving drug [pioglitazone hydrochloride, rosiglitazone, etc.], anα-glucosidase inhibitor [voglibose, acarbose, miglitol, emiglitateetc.], biguanide [phenformin, metformin, buformine etc.], insulinsecretagogue [tolbutamide, glibenclamide, gliclazide, nateglinide,mitiglinide, glimepiride etc.], a dipeptidylpeptidase IV inhibitor[Alogliptin benzoate, Vidagliptin (LAF237), P32/98, Saxagliptin(BMS-477118) etc.], glucose sensitivity insulin secretagogue (TAK-875etc.), GPR40 agonist, GK activator, SGLT inhibitor (dapagliflozin,remogliflozin etc.), Kinedak, Penfill, Humulin, Euglucon, Glimicron,Daonil, Novolin, Monotard, Glucobay, Dimelin, Rastinon, Bacilcon,Deamelin S, Iszilin family, or the like.

In addition, the compound can be also used together with otherpharmaceutical components, including a bone disease medicine, amyocardial protective drug, a coronary artery disease medicine, achronic cardiac failure medicine, a hypothyroidism medicine, a nephroticsyndrome medicine, a chronic renal failure medicine, a gynecologicaldisease medicine, an infection medicine, or the like.

The administration mode may be exemplified by (1) administration of asingle preparation obtained by simultaneously formulating the compoundof the present invention and the combination drug, (2) simultaneousadministration through the same administration route of two preparationsobtained by separately formulating the compound of the present inventionand the combination drug, (3) administration with a time intervalthrough the same administration route of two preparations obtained byseparately formulating the compound of the present invention and thecombination drug, (4) simultaneous administration through differentadministration routes of two preparations obtained by separatelyformulating the compound of the present invention and the combinationdrug, (5) administration with a time interval through differentadministration routes of two preparations obtained by separatelyformulating the compound of the present invention and the combinationdrug (e.g., administration in order of the compound of the presentinvention and then the combination drug, or administration in thereverse order), or the like. The amount of the combination drug to beadministered can be appropriately selected with reference to theclinically used dosage. The mixing ratio of the compound of the presentinvention and the combination drug can be appropriately selected inaccordance with the subject of administration, administration route,disease to be treated, symptoms, combination, and the like.

The compound of the present invention can be also used in combinationwith, for example, gene therapy involving VEGF, TNFα or the like, ortherapeutic methods involving various antibody medicines or the like.

The compound of the present invention can be safely administeredindividually, or according to ordinary methods (e.g., methods describedin the Japanese Pharmacopeia, etc.), as a pharmaceutical compositionmixed with pharmaceutically acceptable carriers, for example, a tablet(including a sugar-coated tablet and a film-coated tablet), a film, apowder, a granule, a capsule, a liquid, an emulsion, a suspension, aninjectable preparation, a suppository, a sustained release preparation,a patch and the like, either orally or parenterally (e.g., topical,rectal, intravenous administration, etc.).

The dosage form of the aforementioned pharmaceutical preparation may beexemplified by oral preparations such as a tablet (including asublingual tablet and a buccal disintegration tablet), a film (includinga buccal disintegration film), a capsule (including a soft capsule and amicrocapsule), a granule, a powder, a troche, a syrup, an emulsion, asuspension and the like; and parenteral preparations such as aninjectable preparation (e.g., a subcutaneous injectable preparation, anintravenous injectable preparation, intramuscular injectablepreparation, intraperitoneal injectable preparation, a drip infusion),external preparation (e.g., a percutaneous preparation, an ointment), asuppository (e.g., a rectal suppository, a vaginal suppository), apellet, a transnasal preparation, a transpulmonary preparation(inhalant), an eye drop and the like.

These preparations may be controlled release preparations such as arapid release preparation, a sustained release preparation and the like(e.g., a sustained release microcapsule).

The content of the compound of the present invention in thepharmaceutical composition is about 0.01 to 100% by weight of the entirecomposition.

The amount of administration of the compound of the present inventionmay vary depending on the subject of administration, administrationroute, subject disease or the like; however, in the case ofadministering orally to an adult as a hypertension medicine, the amountof administration is about 0.0005 to 2 mg/kg of body weight, preferablyabout 0.001 to 1 mg/kg of body weight, and more preferably about 0.001to 0.5 mg/kg of body weight, in terms of compound (I) or (II), theactive ingredient, possibly once to several times a day.

The aforementioned pharmaceutically acceptable carrier may beexemplified by various organic or inorganic carrier materials that areconventionally used as preparation materials, for example, excipient,gliding agent, binding agent and disintegrant for solid preparations; orsolvent, solution aid, suspending agent, isotonic agent, bufferingagent, soothing agent and the like for liquid preparations. Further, ifnecessary, additives such as preservative, antioxidant, colorant,sweetening agent, adsorbing agent, wetting agent and the like can bealso used.

Examples of the excipient include lactose, white sugar, D-mannitol,starch, corn starch, crystalline cellulose, light anhydrous silicic acidand the like.

Examples of the gliding agent include magnesium stearate, calciumstearate, talc, colloidal silica and the like.

Examples of the binding agent include crystalline cellulose, whitesugar, D-mannitol, dextrin, hydroxypropylcellulose,hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose,gelatin, methylcellulose, carboxymethylcellulose sodium and the like.

Examples of the disintegrant include starch, carboxymethylcellulose,carboxymethylcellulose calcium, carboxymethylstarch sodium,L-hydroxypropylcellulose and the like.

Examples of the solvent include water for injection, alcohol, propyleneglycol, Macrogol, sesame oil, corn oil, olive oil and the like.

Examples of the solubilizing agent include polyethylene glycol,propylene glycol, D-mannitol, benzyl benzoate, ethanol,trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodiumcitrate and the like.

Examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid,lecithin, benzalkonium chloride, benzetonium chloride, glycerinmonostearate and the like; hydrophilic polymers such as polyvinylalcohol, polyvinylpyrrolidone, carboxymethylcellulose sodium,methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose and the like; and the like.

Examples of the isotonic agent include glucose, D-sorbitol, sodiumchloride, glycerin, D-mannitol and the like.

Examples of the buffering agent include buffer solutions such asphosphates, acetates, carbonates, citrates and the like.

Examples of the soothing agent include benzyl alcohol and the like.

Examples of the preservative include parahydroxybenzoic acid esters,chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid,sorbic acid and the like.

Examples of the antioxidant include sulfites, ascorbic acid,α-tocopherol and the like.

Examples of the colorant include water-soluble Food coal tar dyes (e.g.,Food dyes such as Food Red No. 2 and No. 3, Food Yellow No. 4 and No. 5,Food Blue No. 1 and No. 2, and the like), water-insoluble lake dyes(e.g., aluminum salts of the aforementioned water-soluble Food coal tardyes), natural dyes (e.g., β-carotene, chlorophyll, red iron oxide) andthe like.

Examples of the sweetening agent include saccharin sodium, dipotassiumglycyrrhizinate, aspartame, stevia and the like.

EXAMPLES

The present invention is explained in detail in the following byreferring to Reference Examples, Examples, Preparation Examples andExperimental Examples, which are not to be construed as limitative. Ofthe synthesis starting materials used in Reference Examples andExamples, synthesis methods of known compounds are omitted.

“Room temperature” in the following Reference Examples and Examplesrepresents a temperature of about 10° C. to about 35° C., and “%”represents weight % unless otherwise stated. Provided that, yieldrepresents mol/mol %.

¹H-NMR spectra were measured with a Varian MERCURY 300 (300 MHz)spectrometer or a BRUKER ADVANCE 300 spectrometer (300 MHz) usingtetramethylsilane as an internal standard. All of the δ values arerepresented in ppm.

LC/MS spectra were measured under the following conditions (condition 1or 2).

Condition 1: Equipment: Agilent 1100 HPLC (Gilson 215autosampler)/Waters ZQ, or Waters 2795/ZQ

Column: CapcellPak C18UG120 (1.5 mmID×35 mL, S-3 μm), manufactured byShiseido Co., Ltd.

solvent: SOLUTION A (0.05% trifluoroacetic acid-containing water),SOLUTION B (0.04% trifluoroacetic acid-containing water)

gradient cycle: 0.00 min (A/B=90/10), 2.00 min (A/B=5/95), 2.75 min(A/B=5/95), 2.76 min (A/B=90/10), 3.45 min (A/B=90/10)

flow rate: 0.5 ml/min

detection: UV (220 nm)

Mass spectrum: electrospray method (ESI)

condition 2: Measurement instrument: LC-MS system, Waters Corporation

HPLC part: HP1100, Agilent Technologies, Inc.

MS part: Micromass ZMD

HPLC Conditions

Column: CAPCELL PAK C18UG120, S-3 μm, 1.5×35 mm (Shiseido Co., Ltd.)

Solvent: Solution A; 0.05% trifluoroacetic acid-containing water,Solution B; 0.04% trifluoroacetic acid-containing acetonitrile

Gradient cycle: 0.00 min (Solution A/Solution B=90/10), 2.00 min(Solution A/Solution B=5/95), 2.75 min (Solution A/Solution B=5/95),2.76 min (Solution A/Solution B=90/10), 3.60 min (Solution A/SolutionB=90/10)

Injection volume: 2 μL, Flow rate: 0.5 mL/min,

Detection method: UV 220 nm

MS Conditions

Ionization method: ESI

For reversed-phase preparative HPLC, Gilson Inc. UniPoint Systemequipped with YMC CombiPrep ODS-A (20 mmID×50 mL, S-5 μm) column wasused, and elution was performed using 0.1% trifluoroaceticacid-containing acetonitrile-water (10:90-100:0) at flow rate of 25ml/min. Alternatively, the reversed-phase preparative HPLC was performedunder the following conditions.

Equipment: Gilson Inc., High Throughput Purification System

Column: YMC Combi Prep Hydro Sphere S-5 μm, 19×50 mm

Solvent: Solution A; 0.1% trifluoroacetic acid-containing water,Solution B; 0.1% trifluoroacetic acid-containing acetonitrile

Gradient cycle: 0.00 min (Solution A/Solution B=95/5), 1.00 min(Solution A/Solution B=95/5), 5.20 min (Solution A/Solution B=5/95),6.40 min (Solution A/Solution B=5/95), 6.50 min (Solution A/SolutionB=95/5), 6.60 min (Solution A/Solution B=95/5)

Flow rate: 20 mL/min, Detection method: UV 220 nm

The microwave reactor used was Discover of CEM.

Other symbols used in the present text indicate the following.

s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, dt:double triplet, td: triple doublet, dq: double quartet, tq: triplequartet, ddd: double double doublet, m: multiplet, br: broad, quin:quintet.

DMF: N,N-dimethylformamide, DMA: N,N-dimethylacetamide, DMSO: dimethylsulfoxide, THF: tetrahydrofuran.

HOBt: 1-hydroxybenzotriazole monohydrate, WSC.HCl:1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride.

TFA: trifluoroacetic acid.

MSA: methanesulfonic acid, DIEA: N-ethyldiisopropylamine, M: moleconcentration.

Reference Example 1 dimethylpyridine-3,5-dicarboxylate

Pyridine-3,5-dicarboxylic acid (25.5 g) was suspended in methanol (184ml), and thionyl chloride (33.8 ml) was added dropwise at roomtemperature. The reaction mixture was stirred with heating under refluxfor 3 hr, and the mixture was allowed to cool to room temperature andconcentrated under reduced pressure. The residue was diluted with water,and the mixture was extracted with ethyl acetate. The aqueous layer wasneutralized with 8M aqueous sodium hydroxide solution, and extractedwith ethyl acetate. The extract was washed successively with saturatedaqueous sodium hydrogen carbonate solution and saturated brine, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure to give the object product (27.9 g) as a powder.

¹H-NMR (CDCl₃) δ 4.00 (6H, s), 8.88 (1H, t), 9.37 (2H, d)

Reference Example 2(3RS,5SR)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)piperidine-3-carboxylicacid and(3RS,5RS)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)piperidine-3-carboxylicacid and 1-tert-butyl 3,5-dimethyl piperidine-1,3,5-tricarboxylate

Dimethylpyridine-3,5-dicarboxylate (15 g) was dissolved in methanol (150ml), and 6M hydrochloric acid (19 ml) and rhodium-carbon (1.5 g) wereadded. The reaction mixture was stirred under hydrogen pressurization (5atm) at 50° C. for 25 hr. The mixture was allowed to cool to roomtemperature, the rhodium catalyst was filtered off and the filtrate wasconcentrated under reduced pressure. The residue was dissolved inethanol (100 ml), and triethylamine (16 ml) and di-tert-butylbicarbonate (18.5 g) were successively added under ice-cooling. Thereaction mixture was stirred at room temperature for 15 hr, andconcentrated under reduced pressure. The residue was dissolved in 0.5Mhydrochloric acid and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure. The residuewas subjected to silica gel column chromatography, and fractions elutedwith hexane-ethyl acetate (7:1-1:4) were obtained. A less polar fractionwas concentrated under reduced pressure to give 1-tert-butyl3,5-dimethyl piperidine-1,3,5-tricarboxylate (15.2 g). A highly-polarfraction was concentrated under reduced pressure, and the residue wasdiluted with ethyl acetate. The precipitate was collected by filtrationand washed with ethyl acetate to give(3RS,5SR)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)piperidine-3-carboxylicacid (2.1 g) as a powder. The filtrate was concentrated under reducedpressure to give a mixture (4.2 g) of(3RS,5SR)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)piperidine-3-carboxylicacid and(3RS,5RS)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)piperidine-3-carboxylicacid.

(3RS,5SR)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)piperidine-3-carboxylicacid

¹H-NMR (CDCl₃) δ 1.47 (9H, s), 1.72 (1H, d), 2.41-2.63 (3H, m), 2.72(2H, br s), 3.71 (3H, s), 4.38 (2H, d)

mixture of(3RS,5SR)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)piperidine-3-carboxylicacid and(3RS,5RS)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)piperidine-3-carboxylicacid

¹H-NMR (CDCl₃) δ 1.44-1.47 (9H, m), 1.60-1.82 (1H, m), 2.10 (1H, br s),2.38-2.61 (3H, m), 2.72 (2H, br s), 3.71 (3H, s), 4.38 (2H, br s)

1-tert-butyl 3,5-dimethyl piperidine-1,3,5-tricarboxylate

¹H-NMR (CDCl₃) δ 1.45-1.49 (9H, m), 1.63-1.76 (1H, m), 2.07 (1H, br s),2.38-2.55 (2H, m), 2.61-2.89 (2H, m), 3.70 (6H, s), 4.35 (2H, br s)

Reference Example 3(3S,5R)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)piperidine-3-carboxylicacid

A mixture of(3RS,5SR)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)piperidine-3-carboxylicacid (6.16 g), (R)-(+)-1-phenylethylamine (2.60 g) and ethanol (24 ml)was dissolved by heating to 70° C., and recrystallized. The precipitatedcrystals were collected by filtration, dissolved in ethanol (7 ml) againand recrystallized. The precipitated crystals were collected byfiltration, the obtained crystals were suspended in water, acidified byadding saturated aqueous potassium hydrogen sulfate solution, and themixture was extracted 3 times with ethyl acetate. The extract was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure to give the object product(915 mg) as a powder.

specific optical rotation [α]20D:−6.2° (after drying, 20.12 mg,methanol, 2 ml, 100 mm)

¹H-NMR (DMSO-d₆) δ 1.39 (9H, s), 1.52 (1H, q), 2.18-2.54 (3H, m),2.55-2.78 (2H, m), 3.63 (3H, s), 4.03-4.23 (2H, m), 12.51 (1H, br s)

Reference Example 4(3R,5S)-1-(tert-butoxycarbonyl)piperidine-3,5-dicarboxylic acid

Dimethylpyridine-3,5-dicarboxylate (62.8 g) was dissolved in acetic acid(300 mL), 5% rhodium-carbon (6 g) was added and the mixture was stirredunder hydrogen pressurization (5 atm) at 50° C. for 20 hr. The reactionmixture was allowed to cool to room temperature, the rhodium catalystwas filtered off, and the filtrate was concentrated under reducedpressure. The residue was dissolved in methanol (300 mL), andtriethylamine (180 mL) and di-tert-butyl bicarbonate (105 g) weresuccessively added under ice-cooling. The reaction mixture was stirredat room temperature for 15 hr, and concentrated under reduced pressure.The residue was dissolved in water, and the mixture was adjusted to pH 3with 6M hydrochloric acid and extracted with ethyl acetate. The ethylacetate extraction layer was washed with saturated brine, and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure. The residue was dissolved in methanol (300 mL), and 8N aqueoussodium hydroxide solution (161 mL) was added dropwise at roomtemperature. The reaction mixture was stirred at room temperature for 20hr, and methanol was evaporated under reduced pressure. The concentratewas diluted with saturated aqueous sodium hydrogen carbonate solution(100 ml) and washed twice with diethyl ether. The basic aqueous layerwas acidified (pH 3) with 6M hydrochloric acid. The precipitated powderwas collected by filtration, washed with water and air-dried to give theobject product (80.5 g) as a powder.

¹H-NMR (DMSO-d₆) δ 1.34-1.43 (9H, m), 1.48 (1H, m), 2.15-2.42 (3H, m),2.59-2.72 (2H, m),4.13 (2H, d)

Reference Example 5(3S,5R)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)piperidine-3-carboxylicacid

(3R,5S)-1-(tert-Butoxycarbonyl)piperidine-3,5-dicarboxylic acid (113 g)was suspended in acetic anhydride (1000 ml), and the mixture was heatedunder reflux for 3 hr and concentrated under reduced pressure. Toluene(100 ml) was added to the residue and the mixture was concentrated underreduced pressure. Toluene (100 ml) was added again and the mixture wasconcentrated under reduced pressure. A similar reaction was repeatedtwice to give a residue (209 g). The obtained residue (51 g) andquinidine (71 g) were dissolved in THF (900 ml), and the mixture wascooled to −40° C. A solution of methanol (81 ml) in THF (100 ml) wasadded dropwise over 30 min, and the mixture was stirred at the sametemperature for 6 hr. THF (about 700 ml) was evaporated under reducedpressure, ethyl acetate was added and the mixture was washed with 2Nhydrochloric acid. The aqueous layer was extracted with ethyl acetate,and the organic layers were combined, washed successively with 2Nhydrochloric acid and saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was concentrated under reduced pressure.A similar reaction was repeated 3 times and the obtained residue (216 g)was suspended in ethanol (835 ml). (R)-(+)-1-Phenylethylamine (91 g) wasadded and dissolved by heating the mixture to 70° C. The hot ethanolsolution was quickly filtered, and the filtrate was stood still at roomtemperature for 12 hr. The precipitated colorless crystals werecollected by filtration, washed successively with ethyl acetate-hexaneand hexane, and air dried. The obtained solid was suspended in water,saturated aqueous potassium hydrogen sulfate solution was added and themixture was extracted 3 times with ethyl acetate. The organic layer waswashed with saturated brine, dried over anhydrous magnesium sulfate andconcentrated to dryness to give the object product (148 g) as a solid.

¹H-NMR (DMSO-d₆) δ 1.39 (9H, s), 1.52 (1H, q), 2.18-2.54 (3H, m),2.55-2.78 (2H, m), 3.63 (3H, s), 4.03-4.23 (2H, m), 12.51 (1H, br s)

Reference Example 6 1-tert-butyl3-methyl(3R,5S)-5-aminopiperidine-1,3-dicarboxylate

(3S,5R)-1-(tert-Butoxycarbonyl)-5-(methoxycarbonyl)piperidine-3-carboxylicacid (2.83 g) was suspended in toluene (36 ml), diphenylphosphoryl azide(2.60 ml) and triethylamine (1.70 ml) were added, and the mixture wasstirred at 100° C. for 1 hr. The reaction mixture was cooled to roomtemperature, benzyl alcohol (1.53 ml) and triethylamine (7.00 ml) wereadded and the mixture was stirred at 80° C. for 3 hr. The reactionmixture was concentrated, the residue was dissolved in ethyl acetate,and the solution was washed with water, 0.5M hydrochloric acid, andsaturated brine in this order, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure. The residuewas subjected to silica gel column chromatography, and a fraction elutedwith ethyl acetate-hexane (1:3-3:1) was concentrated under reducedpressure. The obtained residue was dissolved in methanol (60 ml), 10%palladium carbon (50% in water) (150 mg) was added and the mixture wasstirred under a hydrogen pressurization (5 atom) at ambient temperaturefor 5 hr. The catalyst was filtered off, and the filtrate wasconcentrated under reduced pressure to give the object product (1.83 g)as an oil.

¹H-NMR (CDCl₃) δ 1.22-1.43 (4H, m), 1.46 (9H, s), 2.27-2.79 (4H, m),3.70 (3H, s), 4.13 (2H, br s)

In the same manner as in the method shown in Reference Example 6, thefollowing compound (Reference Example 7) was obtained.

Reference Example 7 1-tert-butyl 3-methyl5-aminopiperidine-1,3-dicarboxylate

¹H-NMR (CDCl₃) δ 1.19-1.41 (3H, m), 1.46-1.50 (9H, m), 1.82-2.78 (4H,m), 3.49 (1H, m), 3.64-3.73 (3H, m), 4.15 (2H, br s)

Reference Example 8 1-tert-butyl3-methyl(3R,5S)-5-[(2-methylpropyl)amino]piperidine-1,3-dicarboxylate

1-tert-Butyl 3-methyl(3R,5S)-5-aminopiperidine-1,3-dicarboxylate (1.83g), isobutyraldehyde (0.78 ml) and acetic acid (0.49 ml) were dissolvedin methanol (50 ml), and the mixture was stirred at room temperature for30 min. Sodium triacetoxyborohydride (3.80 g) was added to the reactionmixture, and the mixture was stirred at room temperature for 7 hr. Thereaction mixture was concentrated under reduced pressure, theconcentrate was basified with aqueous sodium bicarbonate, and extractedwith ethyl acetate. The extract was washed with water and saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The residue was subjected to silicagel column chromatography, and a fraction eluted with ethylacetate-hexane (1:1)-ethyl acetate 100%-ethyl acetate-methanol (9:1) wasconcentrated under reduced pressure to give the object product (1.42 g)as an oil.

¹H-NMR (CDCl₃) δ 0.90 (6H, d), 1.22-1.38 (3H, m), 1.46 (9H, s), 1.69(1H, dt), 2.23-2.39 (2H, m), 2.44-2.59 (1H, m), 2.47 (2H, d), 2.74 (1H,br s), 3.69 (3H, s), 4.18-4.34 (2H, m)

In the same manner as in the method shown in Reference Example 8, thefollowing compound (Reference Example 9) was obtained.

Reference Example 9 1-tert-butyl 3-methyl5-[(2-methylpropyl)amino]piperidine-1,3-dicarboxylate

¹H-NMR (CDCl₃) δ 0.93-1.09 (2H, m), 1.02 (4H, d), 1.45 (9H, d), 2.05(3H, s), 2.65-2.79 (2H, m), 2.83-2.98 (1H, m), 3.25 (1H, dd), 3.49 (2H,s), 3.58-3.75 (3H, m), 3.94 (1H, d)

Reference Example 10 ethyl1-(4-methoxybutyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate

A solution of ethyl 7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate(207 mg), 4-methoxybutyl methanesulfonate (273 mg) and cesium carbonate(652 mg) in N,N-dimethylacetamide (10 ml) was stirred at 60° C. for 15hr. After cooling to room temperature, the reaction mixture was dilutedwith water and extracted with ethyl acetate (10 ml×2). The extract waswashed with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wassubjected to silica gel column chromatography, and a fraction elutedwith ethyl acetate-hexane (5:95-3:7) was concentrated under reducedpressure to give the object product (250 mg).

MS (ESI+, m/e) 294 (M+1)

Reference Example 111-(4-methoxybutyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylic acid

Ethyl1-(4-methoxybutyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate (250mg) and lithium hydroxide monohydrate (54 mg) were dissolved in ethanol(4 ml) and water (2 ml), and the mixture was stirred at 60° C. for 3 hr.The solvent was concentrated under reduced pressure, and the residue wasneutralized with 1N hydrochloric acid, extracted with ethyl acetate (10ml×2), and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The residue was subjected to silicagel column chromatography, and a fraction eluted with ethylacetate-hexane (5:95-3:7) was concentrated under reduced pressure togive the object product (215 mg).

MS (ESI+, m/e) 266 (M+1)

Reference Example 12 4-methoxybutyl1-(4-methoxybutyl)-4,5,6,7-tetrahydro-1H-indole-2-carboxylate

A solution of 4,5,6,7-tetrahydro-1H-indole-2-carboxylic acid (280 mg),4-methoxybutyl methanesulfonate (775 mg) and cesium carbonate (2.77 g)in N,N-dimethylacetamide (25 ml) was stirred at 65° C. for 15 hr. Aftercooling to room temperature, the reaction mixture was diluted with waterand extracted with ethyl acetate (20 ml×2). The extract was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The residue was subjected tosilica gel column chromatography, and a fraction eluted with ethylacetate-hexane (5:95-3:7) was concentrated under reduced pressure togive the object product (375 mg).

MS (ESI+, m/e) 338 (M+1)

In the same manner as in Reference Example 11, the following compound(Reference Example 13) was obtained.

Reference Example 131-(4-methoxybutyl)-4,5,6,7-tetrahydro-1H-indole-2-carboxylic acid

MS (ESI+, m/e) 252 (M+1)

Reference Example 14 1-(4-methoxybutyl)-1H-indole-2-carboxylic acid

Methyl 1H-indole-2-carboxylate (0.67 g), cesium carbonate (1.9 g) and4-methoxybutyl methanesulfonate (0.70 g) were suspended in DMA (20 ml),and the suspension was stirred at 60° C. for 4 hr. The reaction mixturewas concentrated under reduced pressure, the residue was diluted withwater, and the mixture was extracted with ethyl acetate. The extract waswashed with saturated brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The obtained residue was subjectedto silica gel chromatography, and a fraction eluted with ethylacetate-hexane (0:10-4:6) was concentrated under reduced pressure. Theobtained residue was dissolved in methanol (10 ml), 4N aqueous sodiumhydroxide solution (5 ml) was added, and the mixture was heated at 80°C. for 2 hr. The mixture was allowed to cool to room temperature,acidified with 1N aqueous hydrochloric acid and extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure togive the object product (0.77 g).

¹H-NMR (DMSO-d₆) δ 1.32-1.53 (2H, m), 1.63-1.79 (2H, m), 3.18 (3H, s),3.28 (2H, t), 4.59 (2H, t), 7.11 (1H, s), 7.23 (1H, d), 7.32 (1H, s),7.58 (1H, dd), 7.67 (1H, d)

MS (ESI+, m/e) 248 (M+1)

Reference Example 15 tert-butyl(3S,5R)-3-[{[1-(4-methoxybutyl)-1H-indol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

1-(4-Methoxybutyl)-1H-indole-2-carboxylic acid (210 mg), tert-butyl(3S,5R)-3-[(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(270 mg) and N,N-diisopropylethylamine (5601) were dissolved in1,2-dichloroethane (10 ml), chloro-N,N,N′,N′-tetramethylformamidiniumhexafluorophosphate (360 mg) was added, and the mixture was stirred atroom temperature for 2 hr. The reaction mixture was concentrated, andthe residue was subjected to silica gel column chromatography, and afraction eluted with ethyl acetate-hexane (0:10-10:0) was concentratedunder reduced pressure to give the object product (83 mg).

MS (ESI+, m/e) 599 (M+1)

Reference Example 16 methyl2-[(tert-butoxycarbonyl)(4-methoxybutyl)amino]-3-nitrobenzoate

Methyl 2-[(tert-butoxycarbonyl)amino]-3-nitrobenzoate (3.0 g),4-methoxybutyl methanesulfonate (2.0 g) and potassium carbonate (2.1 g)were dissolved in DMF (30 ml), and the mixture was stirred at 60° C.overnight. The reaction mixture was concentrated, aqueous potassiumcarbonate solution was added, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The residue was subjected to silica gel column chromatography,and a fraction eluted with ethyl acetate-hexane (0:10→8:2) wasconcentrated under reduced pressure to give the object product (2.9 g).

¹H-NMR (CDCl₃) δ 1.28-1.34 (9H, m), 1.47-1.61 (6H, m), 3.28 (3H, s),3.30-3.40 (2H, m), 3.90-3.95 (3H, m), 7.49 (1H, s), 7.91-8.02 (1H, m),8.04-8.16 (1H, m)

Reference Example 17 methyl1-(4-methoxybutyl)-2-(trichloromethyl)-1H-benzimidazole-7-carboxylate

Methyl 2-[(tert-butoxycarbonyl)(4-methoxybutyl)amino]-3-nitrobenzoate(2.9 g) was dissolved in methanol (30 ml), palladium-carbon (5%, 500 mg)was added, and the mixture was stirred for 3 hr under a hydrogenatmosphere. The reaction mixture was filtered through celite, and thefiltrate was concentrated under reduced pressure. The residue (1.8 g)was dissolved in acetic acid (40 ml), methyl 2,2,2-trichloroethanimidate(0.88 ml) was added, and the mixture was stirred at 50° C. for 6 hr. Thereaction mixture was poured into water, and the mixture was extractedwith ethyl acetate. The extract was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure to give the object product (2.6 g).

¹H-NMR (CDCl₃) δ 1.71 (4H, br s), 3.31 (3H, s), 3.37 (2H, t), 4.00 (3H,s), 4.91 (1H, dd), 4.92 (1H, d), 7.36 (1H, t), 7.83 (1H, dd), 8.06 (1H,dd)

Reference Example 18 methyl3-[(2-methoxyethoxy)methyl]imidazo[1,2-a]pyridine-2-carboxylate

To a solution of methyl3-(hydroxymethyl)imidazo[1,2-a]pyridine-2-carboxylate (0.30 g) in DMF (5ml) was added sodium hydride (60 mg) under ice-cooling. The mixture wasstirred at room temperature for 30 min, 2-methoxyethyl bromide (220 mg)was added under ice-cooling, and the mixture was stirred at 60° C. for 3hr. The reaction mixture was concentrated under reduced pressure, andthe residue was diluted with aqueous potassium carbonate, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The obtained residue was subjected to silica gelchromatography, and a fraction eluted with ethyl acetate-hexane(0:10-10:0) was concentrated under reduced pressure to give the objectproduct (0.16 g).

¹H NMR (CDCl₃) δ 3.42 (3H, s), 3.48-3.57 (2H, m), 3.65 (2H, dd),3.95-4.00 (3H, m), 5.31 (2H, d), 6.88 (1H, dd), 7.26 (1H, dd), 7.66 (1H,dt), 8.07-8.20 (1H, m)

MS (ESI+, m/e) 265 (M+1)

Reference Example 19 1-tert-butyl3-methyl(3R,5S)-5-{[(benzyloxy)carbonyl]amino}piperidine-1,3-dicarboxylate

(3S,5R)-1-(tert-Butoxycarbonyl)-5-(methoxycarbonyl)piperidine-3-carboxylicacid (2.83 g) was suspended in toluene (36 ml), diphenylphosphoryl azide(2.60 ml) and triethylamine (1.70 ml) were added and the mixture wasstirred at 100° C. for 1 hr. The reaction mixture was cooled to roomtemperature, benzyl alcohol (1.53 ml) and triethylamine (7.00 ml) wereadded and the mixture was stirred at 80° C. for 3 hr. The reactionmixture was concentrated, the residue was dissolved in ethyl acetate,washed with water, 0.5M hydrochloric acid and saturated brine in thisorder, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The residue was subjected to silicagel column chromatography, and a fraction eluted with ethylacetate-hexane (1:3-3:1) was concentrated under reduced pressure to givethe object product (2.79 g) as an oil.

MS (ESI+, m/e) 393 (M+1)

Reference Example 20(3R,5S)-5-{[(benzyloxy)carbonyl]amino}-1-(tert-butoxycarbonyl)piperidine-3-carboxylicacid

To a solution (700 ml) of 1-tert-butyl3-methyl(3R,5S)-5-{[(benzyloxy)carbonyl]amino}piperidine-1,3-dicarboxylate(115 g) in methanol was added 1M aqueous sodium hydroxide solution (350ml) under ice-cooling, and the mixture was stirred at room temperaturefor 12 hr. The reaction mixture was concentrated under reduced pressureto about ⅓ volume, and the residual aqueous solution was washed withethyl acetate-hexane (1:1, 600 ml). The aqueous layer was neutralizedwith 1M hydrochloric acid and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure to give the object product (98.5 g).

¹H-NMR (DMSO-d₆) δ: 1.33 (1H, br s), 1.40 (9H, s), 2.09 (1H, d),2.36-2.52 (3H, m), 3.93-4.09 (2H, m), 5.03 (2H, s), 7.28-7.43 (5H, m),12.52 (1H, br s).

Reference Example 21 tert-butyl(3S,5R)-3-{[(benzyloxy)carbonyl]amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

(3R,5S)-5-{[(Benzyloxy)carbonyl]amino}-1-(tert-butoxycarbonyl)piperidine-3-carboxylicacid (49.2 g), morpholine (11.4 ml), 1H-benzotriazol-1-ol (10.0 g) andtriethylamine (40 ml) were dissolved in DMF (250 ml), WSC.HCl (30.0 g)was added, and the mixture was stirred at room temperature for 4 days.The reaction mixture was poured into water, and the mixture wasextracted with ethyl acetate. The extract was washed successively withsaturated aqueous sodium hydrogen carbonate solution and saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure to give the object product (62.9 g).

¹H-NMR (CDCl₃): 1.46 (9H, s), 1.69 (2H, br s), 2.04 (1H, s), 2.73 (2H,br s), 2.79-2.96 (1H, m), 3.52-3.65 (6H, m), 3.69 (2H, d), 3.67 (1H, brs), 4.04 (1H, d), 5.09 (2H, s), 5.40 (1H, br s), 7.25-7.41 (5H, m).

Reference Example 22 tert-butyl(3S,5R)-3-[(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

tert-Butyl(3S,5R)-3-{[(benzyloxy)carbonyl]amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(58 g) and palladium(II) hydroxide-carbon (5 g) were suspended inmethanol (400 ml) and the mixture was stirred under a hydrogenatmosphere (1 atom) at room temperature for 16 hr. The palladiumcatalyst was filtered off, and the filtrate was concentrated underreduced pressure. The obtained residue and acetic acid (8.8 ml) weredissolved in methanol (400 ml), 2-methylpropanal (14.0 ml) was added,and the mixture was stirred at room temperature for 1 hr. Sodiumtriacetoxyborohydride (40.4 g) was added to the reaction mixture, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was concentrated under reduced pressure, and the concentrate wasbasified with 3.5M aqueous potassium carbonate solution, and the mixturewas extracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The residue was subjected to basicsilica gel column chromatography, and a fraction eluted with ethylacetate-hexane (1:5)-ethyl acetate-hexane (1:1) was concentrated underreduced pressure to give the object product (33.3 g).

¹H-NMR (CDCl₃) δ: 0.90 (6H, d), 1.46 (9H, s), 1.54 (1H, d), 1.69 (1H,dt), 1.96-2.12 (2H, m), 2.23-2.37 (1H, m), 2.47 (3H, d), 2.66 (1H, d),3.61 (1H, br s), 3.55 (2H, d), 3.69 (5H, ddd), 4.01-4.46 (2H, m).

Reference Example 23 tert-butyl(3S,5R)-3-[{[1-(4-methoxybutyl)-7-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

1-(4-Methoxybutyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylic acid(210 mg), tert-butyl(3S,5R)-3-[(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(292 mg) and N,N-diisopropylethylamine (550 μl) were dissolved in1,2-dichloroethane (10 ml), chloro-N,N,N′,N′-tetramethylformamidiniumhexafluorophosphate (244 mg) was added, and the mixture was stirred atroom temperature for 15 hr. The reaction mixture was diluted withsaturated aqueous sodium hydrogen carbonate solution and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The residue was subjected to silicagel column chromatography, and a fraction eluted with ethylacetate-hexane (10:90-100:0) was concentrated under reduced pressure togive the object product (245 mg).

MS (ESI+, m/e) 617 (M+1)

In the same manner as in Reference Example 23, the following compound(Reference Example 24) was obtained.

Reference Example 24 tert-butyl(3S,5R)-3-[{[1-(4-methoxybutyl)-4,5,6,7-tetrahydro-1H-indol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 603 (M+1)

Example 11-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-4,5,6,7-tetrahydro-1H-indole-2-carboxamide

tert-Butyl(3S,5R)-3-[{[1-(4-methoxybutyl)-4,5,6,7-tetrahydro-1H-indol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(100 mg) was dissolved in dichloromethane (0.5 ml), TFA (0.5 ml) wasadded, and the mixture was stirred at room temperature for 15 min. Thesolvent was evaporated under reduced pressure, and the residue wasneutralized with saturated aqueous sodium hydrogen carbonate. Themixture was extracted with ethyl acetate (10 ml×2), and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The residue was dried under reduced pressure to give theobject product (45 mg).

MS (ESI+, m/e) 503 (M+1)

Example 21-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamidemonohydrochloride

tert-Butyl(3S,5R)-3-[{[1-(4-methoxybutyl)-7-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(100 mg) was dissolved in ethyl acetate (1 ml), 4N hydrogenchloride-ethyl acetate solution (1 ml) was added, and the mixture wasstirred at room temperature for 1 hr. The solvent was evaporated underreduced pressure, and the residue was dried under reduced pressure togive the object product (52 mg).

MS (ESI+, m/e) 517 (M+1)

Example 31-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-indole-2-carboxamidehydrochloride

tert-Butyl(3S,5R)-3-[{[1-(4-methoxybutyl)-1H-indol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(83.4 mg) was dissolved in 4N hydrogen chloride-ethyl acetate (3 ml),and the mixture was WO2009/154300 PCT/JP2009/061438 stirred at roomtemperature for 1.5 hr. The reaction mixture was concentrated to givethe object product (67 mg).

MS (ESI+, m/e) 499 (M+1)

Example 43-[(2-methoxyethoxy)methyl]-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]imidazo[1,2-a]pyridine-2-carboxamidedihydrochloride

Methyl 3-[(2-methoxyethoxy)methyl]imidazo[1,2-a]pyridine-2-carboxylate(160 mg) and lithium hydroxide (76 mg) were dissolved in water (10 ml)and methanol (2 ml), and the mixture was stirred at 70° C. for 6 hr. Themixture was allowed to cool to room temperature, acidified with 1Naqueous hydrochloric acid and extracted with ethyl acetate. The extractwas washed with saturated brine, dried over anhydrous magnesium sulfateand concentrated under reduced pressure. The residue, tert-butyl(3S,5R)-3-[(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(130 mg) and N,N-diisopropylethylamine (340 μg) were dissolved in1,2-dichloroethane (10 ml), chloro-N,N,N′,N′-tetramethylformamidiniumhexafluorophosphate (220 mg) was added, and the mixture was stirred atroom temperature for 3 hr. The reaction mixture was concentrated,diluted with aqueous calcium carbonate solution and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The residue was subjected to silicagel column chromatography, and a fraction eluted with ethylacetate-hexane (0:10-10:0) was concentrated under reduced pressure. Theresidue was dissolved in 4N hydrogen chloride-ethyl acetate (1 ml), andthe mixture was stirred at room temperature for 1.5 hr. The reactionmixture was concentrated to give the object product (65 mg).

MS (ESI+, m/e) 502 (M+1)

Example 54-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-4H-thieno[3,2-b]pyrrole-5-carboxamide

4H-Thieno[3,2-b]pyrrole-5-carboxylic acid (160 mg), tert-butyl(3S,5R)-3-[(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(250 mg) and N,N-diisopropylethylamine (630 μl) were dissolved in1,2-dichloroethane (10 ml), chloro-N,N,N′,N′-tetramethylformamidiniumhexafluorophosphate (410 mg) was added, and the mixture was stirred atroom temperature for 3 hr. The reaction mixture was concentrated,diluted with aqueous calcium carbonate solution and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The residue was subjected to silicagel column chromatography, and a fraction eluted with ethylacetate-hexane (0:10-10:0) was concentrated under reduced pressure. Theresidue was dissolved in DMA (10 ml), cesium carbonate (790 mg) and4-methoxybutyl methanesulfonate (230 mg) were added, and the mixture wasstirred at 70° C. overnight. The reaction mixture was concentrated underreduced pressure, the residue was diluted with water, and the mixturewas extracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was dissolved in TFA (1.0 ml), and themixture was stirred at room temperature for 30 min and concentratedunder reduced pressure. This was purified by HPLC, and the objectfraction was concentrated, diluted with aqueous calcium carbonatesolution and the mixture was extracted with ethyl acetate. The extractwas washed with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure to give theobject product (52 mg).

MS (ESI+, m/e) 505 (M+1)

Example 6 methyl 2-{(2-methylpropyl)[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]carbamoyl}-1-(4-methoxybutyl)-3H-benzimidazole-7-carboxylatedihydrochloride

Methyl1-(4-methoxybutyl)-2-(trichloromethyl)-1H-benzimidazole-7-carboxylate(0.44 g) and tert-butyl(3S,5R)-3-[(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(0.3 g) were dissolved in acetonitrile (5.0 ml) and water (5.0 ml),potassium carbonate (2.4 g) was added, and the mixture was stirred at60° C. overnight. The reaction mixture was cooled to room temperature,and the mixture was extracted with ethyl acetate. The extract was washedsuccessively with 10% aqueous citric acid solution, aqueous sodiumbicarbonate and saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure. The residuewas subjected to silica gel column chromatography, and a fraction elutedwith ethyl acetate-hexane (0:10→10:0) was concentrated under reducedpressure, and a fraction eluted with ethyl acetate was concentratedunder reduced pressure. The residue was dissolved in 4N hydrochloricacid-ethyl acetate solution, and the mixture was stirred for 30 min. Thereaction mixture was concentrated, purified by HPLC, and the objectfraction was concentrated, diluted with aqueous calcium carbonatesolution and the mixture was extracted with ethyl acetate. The extractwas washed with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, andconverted to hydrochloride with 4N hydrochloric acid-ethyl acetatesolution to give the object product (9.3 mg).

MS (ESI+, m/e) 558 (M+1)

Example 7(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl(3R,5S)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylatedihydrochloride

(3R,5S)-1-(tert-Butoxycarbonyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid (0.3 g) and 4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one (0.09 g)were dissolved in DMA (3.0 ml), toluenesulfonyl chloride (0.13 g), DMAP(0.014 g) and potassium carbonate (0.1 g) were added with stirring underice-cooling, and the mixture was stirred for 6 hr under ice-cooling, andfurther at room temperature overnight. The reaction mixture wasneutralized with 1N aqueous hydrochloric acid and extracted with ethylacetate. The extract was washed successively with aqueous sodiumbicarbonate and saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure. The residuewas subjected to silica gel column chromatography, and a fraction elutedwith ethyl acetate-hexane (0:10→1:1) was concentrated under reducedpressure, and a fraction eluted with ethyl acetate was concentratedunder reduced pressure. The residue was dissolved in 2N hydrochloricacid-ethyl acetate solution, and the mixture was stirred at roomtemperature for 1 hr. The reaction mixture was concentrated to give theobject product (186 mg).

MS (ESI+, m/e) 543 (M+1)

Example 8methyl(3R,5S)-5-[{[1-(4-methoxybutyl)-1H-indol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylate

1-(4-Methoxybutyl)-1H-indole-2-carboxylic acid (247 mg), 1-tert-butyl3-methyl(3R,5S)-5-[(2-methylpropyl)amino]piperidine-1,3-dicarboxylate(314 mg) and diisopropylethylamine (862 μl) were dissolved in methylenechloride (5 ml), chloro-N,N,N′,N′-tetramethylformamidiniumhexafluorophosphate (337 mg) was added, and the mixture was stirred atroom temperature for 15 hr. The reaction mixture was subjected to silicagel column chromatography, and a fraction eluted with ethylacetate-hexane (3:7) was concentrated under reduced pressure to give1-tert-butyl3-methyl(3R,5S)-5-[{[1-(4-methoxybutyl)-1H-indol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate(40 mg) as an oil. The obtained 1-tert-butyl3-methyl(3R,5S)-5-[{[1-(4-methoxybutyl)-1H-indol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate(40 mg) was dissolved in methanol (2 ml), 4M hydrogen chloride-ethylacetate (2 ml) was added, and the mixture was stirred at roomtemperature for 15 hr. The reaction mixture was concentrated, and theresidue was purified by reversed-phase preparative HPLC, and the objectfraction was concentrated under reduced pressure. An aqueous sodiumbicarbonate solution was added to the residue, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous magnesium sulfate, and concentrated to givethe object product (13 mg).

MS (ESI+, m/e) 444 (M+1)

Reference Example 25 methyl 1-(2-phenylethyl)-1H-indole-2-carboxylate

Methyl 1H-indole-2-carboxylate (526 mg) and (2-bromoethyl)benzene (1.11g) were dissolved in DMA (15 ml), cesium carbonate (2.93 g) was added,and the mixture was stirred at 60° C. for 15 hr. The reaction mixturewas concentrated, and the residue was diluted with aqueous sodiumbicarbonate, and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, dried over anhydrous magnesiumsulfate, and concentrated. The residue was subjected to silica gelcolumn chromatography, and a fraction eluted with ethyl acetate-hexane(3:7) was concentrated under reduced pressure to give the object product(318 mg) as an oil.

MS (ESI+, m/e) 280 (M+1)

Reference Example 26 tert-butyl (3S,5R)-3-[(2-methylpropyl){[1-(2-phenylethyl)-1H-indol-2-yl]carbonyl}amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

Methyl 1-(2-phenylethyl)-1H-indole-2-carboxylate (318 mg) was dissolvedin methanol (5 ml), 2M aqueous sodium hydroxide solution (1.14 ml) wasadded, and the mixture was stirred at room temperature for 17 hr. Theaqueous layer was adjusted to pH 7 with 1M hydrochloric acid, saturatedbrine was added, and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure to give1-(2-phenylethyl)-1H-indole-2-carboxylic acid (300 mg). The obtained1-(2-phenylethyl)-1H-indole-2-carboxylic acid (300 mg), 1-tert-butyl3-methyl(3R,5S)-5-[(2-methylpropyl)amino]piperidine-1,3-dicarboxylate(185 mg) and diisopropylethylamine (431 μl) were dissolved in methylenechloride (5 ml), chloro-N,N,N′,N′-tetramethylformamidiniumhexafluorophosphate (168 mg) was added, and the mixture was stirred atroom temperature for 15 hr. Aqueous sodium bicarbonate was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was subjected to silica gel column chromatography, and afraction eluted with ethyl acetate was concentrated under reducedpressure to give the object product (83 mg).

MS (ESI+, m/e) 617 (M+1)

Example 9N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1-(2-phenylethyl)-1H-indole-2-carboxamidehydrochloride

tert-Butyl(3S,5R)-3-[(2-methylpropyl){[1-(2-phenylethyl)-1H-indol-2-yl]carbonyl}amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(83 mg) was dissolved in 4M hydrogen chloride-ethyl acetate (2 ml), andthe mixture was stirred at room temperature for 15 hr. The reactionmixture was concentrated to give the object product (75 mg).

MS (ESI+, m/e) 517 (M+1)

Reference Example 27 N-(4-methoxybutyl)benzene-1,2-diamine

To a solution of phenylenediamine (10.8 g) and 4-methoxybutylmethanesulfonate (9.11 g) in acetonitrile (100 ml) was added potassiumcarbonate (20.7 g), and the mixture was stirred heated under reflux for15 hr. Water was added to the reaction mixture, and the mixture wasextracted twice with ethyl acetate. The extract was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The residue was subjected tosilica gel column chromatography, and a fraction eluted with ethylacetate-hexane (35:65) was concentrated under reduced pressure to givethe object product (5.44 g).

¹H-NMR (CDCl₃) δ 1.67-1.82 (4H, m), 3.13 (2H, t), 3.24-3.39 (6H, m),3.38-3.50 (2H, m), 6.62-6.74 (3H, m), 6.81 (1H, m).

MS (ESI+, m/e) 195 (M+1)

Reference Example 28 tert-butyl(3S,5R)-3-{[ethoxy(oxo)acetyl](2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

To a solution of tert-butyl(3S,5R)-3-[(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(9.24 g) and diisopropylethylamine (10.5 ml) in DMA (100 ml) was addeddropwise ethyl chloroglyoxylate (3.4 ml) at 0° C. The reaction mixturewas stirred at room temperature for 15 hr, and the reaction mixture wasconcentrated. An aqueous sodium bicarbonate solution was added to theresidue, and the mixture was extracted with ethyl acetate. The extractwas washed with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure. The residuewas subjected to silica gel column chromatography, and a fraction elutedwith ethyl acetate was concentrated under reduced pressure to give theobject product (10.3 g).

¹H-NMR (CDCl₃) δ 0.84-1.00 (6H, m), 1.37 (3H, q), 1.42-1.53 (9H, m),1.80-2.19 (3H, m), 2.26-2.42 (1H, m), 2.59-2.96 (1H, m), 2.97-3.30 (3H,m), 3.37-3.92 (9H, m), 4.01-4.26 (2H, m), 4.26-4.40 (2H, m).

MS (ESI+, m/e) 470 (M+1)

Reference Example 29

{[(3S,5R)-1-(tert-butoxycarbonyl)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl](2-methylpropyl)amino}(oxo)aceticacid

To a solution of tert-butyl(3S,5R)-3-{[ethoxy(oxo)acetyl](2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(10.3 g) in ethanol (40 ml) was added 2M aqueous sodium hydroxidesolution (22 ml), and the mixture was stirred at room temperature for 6hr. The reaction mixture was adjusted to pH 7 with 1M hydrochloric acid,and extracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure to give the object product (10.3 g).

¹H-NMR (CDCl₃) δ 0.78-0.99 (6H, m), 1.37-1.52 (9H, m), 1.79-2.16 (3H,m), 2.38-3.86 (14H, m), 3.93-4.43 (2H, m).

MS (ESI+, m/e) 442 (M+1)

Reference Example 30 tert-butyl(3S,5R)-3-{[({2-[(4-methoxybutyl)amino]phenyl}amino)(oxo)acetyl](2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

{[(3S,5R)-1-(tert-Butoxycarbonyl)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl](2-methylpropyl)amino}(oxo)aceticacid (10.3 g), HOBt (4.13 g) and WSC.HCl (6.28 g) were dissolved in DMF(50 ml), N-(4-methoxybutyl)benzene-1,2-diamine (4.67 g) anddiisopropylethylamine (11.3 ml) were added, and the mixture was stirredat room temperature for 15 hr and at 60° C. for 2 hr. The reactionmixture was concentrated, and the residue was diluted with aqueoussodium bicarbonate, and the mixture was extracted with ethyl acetate.The extract was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The residue was subjected to silica gel column chromatography, and afraction eluted with ethyl acetate was concentrated under reducedpressure to give the object product (9.11 g).

¹H-NMR (CDCl₃) δ 0.86-1.03 (6H, m), 1.37-1.53 (9H, m), 1.70 (4H, d),1.86-2.26 (3H, m), 2.37-2.97 (3H, m), 3.09-3.22 (3H, m), 3.25-3.48 (6H,m), 3.48-3.98 (10H, m), 4.01-4.97 (2H, m), 6.70-6.84 (2H, m), 7.10-7.21(1H, m), 7.35 (1H, dd), 8.47-8.80 (1H, m).

MS (ESI+, m/e) 618 (M+1)

Reference Example 31 tert-butyl(3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylateand1-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamide

tert-Butyl (3S,5R)-3-{[({2-[(4-methoxybutyl)amino]phenyl}amino) (oxo)acetyl](2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(9.11 g) was dissolved in acetic acid (50 ml), and the mixture wasstirred at 80° C. for 15 hr. The reaction mixture was cooled to roomtemperature and concentrated under reduced pressure, the residue wasdiluted with aqueous sodium bicarbonate, and the mixture was extractedwith ethyl acetate. The extract was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The residue was subjected to basic silica gel columnchromatography, and a fraction eluted with ethyl acetate wasconcentrated under reduced pressure to give tert-butyl(3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(5.85 g), and a fraction eluted with ethyl acetate-methanol (85:15) wasconcentrated under reduced pressure to give1-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamide(580 mg).

tert-butyl(3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

¹H-NMR (CDCl₃) δ 0.63-0.80 (2H, m), 0.89-1.07 (4H, m), 1.41-1.59 (9H,m), 1.59-1.80 (2H, m), 1.87-2.23 (4H, m), 2.30-2.98 (3H, m), 3.21-3.46(6H, m), 3.49-3.91 (10H, m), 3.95-4.47 (5H, m), 7.18-7.51 (3H, m),7.56-7.84 (1H, m).

MS (ESI+, m/e) 600 (M+1)

1-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamide

¹H-NMR (CDCl₃) δ 0.64-0.74 (2H, m), 0.95-1.07 (4H, m), 1.43-1.74 (3H,m), 1.84-2.41 (4H, m), 2.48-2.67 (1H, m), 2.67-3.01 (3H, m), 3.03-3.44(8H, m), 3.47-3.78 (9H, m), 4.06-4.46 (3H, m), 7.28-7.47 (3H, m),7.62-7.81 (1H, m).

MS (ESI+, m/e) 500 (M+1)

Example 101-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidedihydrochloride

tert-Butyl(3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(5.85 g) was dissolved in methanol (20 ml), 4M hydrogen chloride-ethylacetate (20 ml) was added, and the mixture was stirred at roomtemperature for 15 hr. The reaction mixture was concentrated, and theresidue was diluted with aqueous sodium bicarbonate, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The residue was subjected to basicsilica gel column chromatography, and a fraction eluted with ethylacetate-methanol (9:1) was concentrated under reduced pressure to give1-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamide(4.40 g). The obtained1-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamide(2.20 g) was dissolved in ethyl acetate (20 ml), 4M hydrogenchloride-ethyl acetate (5 ml) and methanol (20 ml) were added, and themixture was stirred at room temperature for 5 min. The reaction mixturewas concentrated under reduced pressure to give the object product (2.52g).

¹H-NMR (DMSO-d₆) δ 0.63-0.76 (2H, m), 0.85-1.00 (4H, m), 1.40-1.60 (2H,m), 1.68-1.89 (2H, m), 1.93-2.17 (2H, m), 2.20-2.44 (2H, m), 2.81-3.81(20H, m), 4.19-4.39 (3H, m), 7.23-7.46 (2H, m), 7.57-7.81 (2H, m),8.38-9.77 (2H, m).

MS (ESI+, m/e) 500 (M+1)

Reference Example 32 5-fluoro-N-(4-methoxybutyl)-2-nitroaniline

5-Fluoro-2-nitroaniline (1.0 g) was dissolved in THF (20 ml), sodiumhydride (60% in oil, 384 mg) was added, and the mixture was stirred atroom temperature for 30 min. 4-Methoxybutyl methanesulfonate (1.28 g)was added, and the mixture was heated under reflux with stirring for 15hr. The reaction mixture was cooled to room temperature and saturatedbrine was added, and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure. The residuewas subjected to silica gel column chromatography, and a fraction elutedwith ethyl acetate-hexane (30:70) was concentrated under reducedpressure to give the object product (494 mg).

¹H-NMR (CDCl₃) δ 1.66-1.77 (2H, m), 1.78-1.89 (2H, m), 3.25-3.34 (2H,m), 3.36 (3H, s), 3.45 (2H, t), 6.36 (1H, ddd), 6.49 (1H, dd), 8.16-8.27(2H, m).

MS (ESI+, m/e) 243 (M+1)

Reference Example 33 4-fluoro-2-(4-methoxybutylamino)aniline

5-Fluoro-N-(4-methoxybutyl)-2-nitroaniline (494 mg) was dissolved inmethanol (20 ml), 10% palladium carbon (50% in water, 100 mg) was added,and the mixture was stirred under a hydrogen stream at ambienttemperature and normal pressure for hr. The catalyst was filtered off,and the filtrate was concentrated under reduced pressure to give theobject product (451 mg) as an oil.

¹H-NMR (CDCl₃) δ 1.63 (2H, br s), 1.67-1.81 (4H, m), 3.08 (1H, br s),3.10 (2H, t), 3.36 (3H, s), 3.39-3.47 (2H, m), 6.26-6.38 (2H, m), 6.61(1H, dd).

MS (ESI+, m/e) 213 (M+1)

Reference Example 34 tert-butyl(3S,5R)-3-{[({4-fluoro-2-[(4-methoxybutyl)amino]phenyl}amino) (oxo)acetyl](2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

{[(3S,5R)-1-(tert-Butoxycarbonyl)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl](2-methylpropyl)amino}(oxo)acetic acid (221 mg), HOBt (95 mg) and WSC.HCl (144 mg) were dissolvedin DMF (5 ml), 4-fluoro-2-(4-methoxybutylamino)aniline (106 mg) anddiisopropylethylamine (97 μl) were added, and the mixture was stirred atroom temperature for 15 hr and at 60° C. for 2 hr. The reaction mixturewas cooled to room temperature, and concentrated under reduced pressure.The residue was diluted with aqueous sodium bicarbonate and the mixturewas extracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. The residue was subjected to silicagel column chromatography, and a fraction eluted with ethyl acetate wasconcentrated under reduced pressure to give the object product (9.11mg).

¹H-NMR (CDCl₃) δ 0.89-1.01 (6H, m), 1.39-1.53 (9H, m), 1.61-1.79 (4H,m), 1.88-2.19 (2H, m), 3.05-3.21 (4H, m), 3.30-3.37 (5H, m), 3.38-3.49(3H, m), 3.48-3.79 (12H, m), 3.95-4.22 (1H, m), 6.35-6.48 (2H, m),7.11-7.21 (1H, m), 8.52 (1H, s).

MS (ESI+, m/e) 636 (M+1)

Example 116-fluoro-1-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidedihydrochloride

tert-Butyl (3S,5R)-3-{[({4-fluoro-2-[(4-methoxybutyl)amino]phenyl}amino)(oxo)acetyl](2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(294 mg) was dissolved in acetic acid (5 ml), and the mixture wasstirred at 80° C. for 3 days. The reaction mixture was cooled to roomtemperature, 4M hydrogen chloride-ethyl acetate (5 ml) was added to thereaction mixture, and the mixture was stirred at room temperature for 2hr. The reaction mixture was concentrated, and the residue was dilutedwith aqueous sodium bicarbonate, and extracted with ethyl acetate. Theextract was washed with saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure. The residuewas subjected to basic silica gel column chromatography, and a fractioneluted with ethyl acetate-methanol (85:15) was concentrated underreduced pressure. The residue was dissolved in ethyl acetate, 4Mhydrogen chloride-ethyl acetate (1 ml) was added, and the mixture wasconcentrated again to give the object product (113 mg).

¹H-NMR (DMSO-d₆) δ 0.64-0.79 (2H, m), 0.83-1.01 (4H, m), 1.37-1.60 (2H,m), 1.66-1.89 (2H, m), 1.91-2.18 (2H, m), 2.15-2.44 (1H, m), 2.85-3.85(20H, m), 4.30 (3H, t), 7.09-7.25 (1H, m), 7.57-7.79 (2H, m), 8.57 (1H,br s), 9.20-9.42 (1H, m), 9.46-9.81 (1H, m).

MS (ESI+, m/e) 518 (M+1)

Reference Example 356-fluoro-1-(4-methoxybutyl)-2-(trichloromethyl)-1H-benzimidazole

4-Fluoro-2-(4-methoxybutylamino)aniline (4.28 g) was dissolved in aceticacid (100 ml), methyl 2,2,2-trichloroethanimidate (2.49 ml) was addeddropwise, and the mixture was stirred at room temperature for 2 hr. Thereaction mixture was concentrated under reduced pressure, and theresidue was azeotroped with toluene. The residue was subjected to silicagel column chromatography, and a fraction eluted with ethyl acetate wasconcentrated under reduced pressure to give the object product (6.53 g).

¹H-NMR (CDCl₃) δ 1.71-1.84 (2H, m), 2.00-2.14 (2H, m), 3.38 (3H, s),3.48 (2H, t), 4.46-4.59 (2H, m), 7.03-7.16 (2H, m), 7.81 (1H, dd).

MS (ESI+, m/e) 339 (M+1)

Reference Example 36 tert-butyl(3S,5R)-3-[{[6-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

6-Fluoro-1-(4-methoxybutyl)-2-(trichloromethyl)-1H-benzimidazole (1.02g) and tert-butyl(3S,5R)-3-[(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(1.11 g) were dissolved in acetonitrile (50 ml) and water (25 ml),potassium carbonate (4.15 g) was added, and the mixture was stirred at60° C. for 17 hr. The reaction mixture was cooled to room temperature,and the mixture was extracted with ethyl acetate. The extract was washedsuccessively with 10% aqueous citric acid solution, aqueous sodiumbicarbonate and saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure. The residuewas subjected to silica gel column chromatography, and a fraction elutedwith ethyl acetate was concentrated under reduced pressure to give theobject product (595 mg).

¹H-NMR (CDCl₃) δ 0.64-0.82 (3H, m), 0.89-1.05 (3H, m), 1.41-1.60 (9H,m), 1.59-1.78 (2H, m), 1.83-2.24 (3H, m), 2.28-2.99 (3H, m), 3.33 (17H,d), 3.96-4.43 (5H, m), 7.00-7.17 (2H, m), 7.49-7.75 (1H, m).

MS (ESI+, m/e) 618 (M+1)

Example 126-fluoro-1-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidedihydrochloride

tert-Butyl(3S,5R)-3-[{[6-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylatewas dissolved in 4M hydrogen chloride-ethyl acetate (5 ml), and themixture was stirred at room temperature for 4 hr. The reaction mixturewas concentrated to give the object product (567 mg).

¹H-NMR (DMSO-d₆) δ 0.64-0.79 (2H, m), 0.83-1.01 (4H, m), 1.37-1.60 (2H,m), 1.66-1.89 (2H, m), 1.91-2.18 (2H, m), 2.15-2.44 (1H, m), 2.85-3.85(20H, m), 4.30 (3H, t), 7.09-7.25 (1H, m), 7.57-7.79 (2H, m), 8.57 (1H,br s), 9.20-9.42 (1H, m), 9.46-9.81 (1H, m).

MS (ESI+, m/e) 518 (M+1)

Reference Example 37 1-tert-butyl3-methyl(3R,5S)-5-[{[6-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylateand(3R,5S)-1-(tert-butoxycarbonyl)-5-[{[6-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid

6-Fluoro-1-(4-methoxybutyl)-2-(trichloromethyl)-1H-benzimidazole (3.40g) and 1-tert-butyl3-methyl(3R,5S)-5-[(2-methylpropyl)amino]piperidine-1,3-dicarboxylate(3.14 g) were dissolved in acetonitrile (100 ml) and water (50 ml),cesium carbonate (32.6 g) was added, and the mixture was stirred at 60°C. for 17 hr. The reaction mixture was cooled to room temperature,adjusted to pH 7 with 1M hydrochloric acid, and extracted with ethylacetate. The extract was washed with saturated brine, and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure. The residue was subjected to silica gel column chromatography,and a fraction eluted with ethyl acetate-hexane (1:1) was concentratedunder reduced pressure to give 1-tert-butyl3-methyl(3R,5S)-5-[{[6-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate(1.60 g), and a fraction eluted with ethyl acetate was concentratedunder reduced pressure to give(3R,5S)-1-(tert-butoxycarbonyl)-5-[{[6-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid (1.36 g).

1-tert-butyl3-methyl(3R,5S)-5-[{[6-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate

¹H-NMR (CDCl₃) δ 0.70-0.82 (4H, m), 1.00 (2H, d), 1.29-1.36 (3H, m),1.44-1.52 (6H, m), 1.58-1.72 (2H, m), 1.72-2.04 (3H, m), 2.12-2.37 (1H,m), 2.42-2.93 (3H, m), 3.28-3.80 (12H, m), 4.15-4.51 (4H, m), 7.00-7.14(2H, m), 7.59-7.77 (1H, m).

MS (ESI+, m/e) 563 (M+1)

(3R,5S)-1-(tert-butoxycarbonyl)-5-[{[6-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid

¹H-NMR (CDCl₃) δ 0.69-0.83 (4H, m), 0.95-1.07 (2H, m), 1.16-1.30 (3H,m), 1.42-1.55 (6H, m), 1.60-1.73 (3H, m), 1.75-2.10 (5H, m), 2.40-2.94(2H, m), 3.29-3.68 (10H, m), 4.15-4.36 (2H, m), 7.02-7.18 (2H, m),7.86-8.07 (1H, m).

MS (ESI+, m/e) 549 (M+1)

Reference Example 38(3R,5S)-(tert-butoxycarbonyl)-5-[{[6-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid

1-tert-Butyl3-methyl(3R,5S)-5-[{[6-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate(1.6 g) was dissolved in ethanol (100 ml), 2M aqueous sodium hydroxidesolution (14.2 ml) was added, and the mixture was stirred at 50° C. for5 hr. The reaction mixture was cooled to room temperature, adjusted topH 7 with 1M hydrochloric acid, and extracted with ethyl acetate. Theextract was washed with saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure. The residuewas subjected to silica gel column chromatography, and a fraction elutedwith ethyl acetate was concentrated under reduced pressure to give theobject product (1.55 g).

¹H-NMR (CDCl₃) δ 0.69-0.83 (4H, m), 0.95-1.07 (2H, m), 1.16-1.30 (3H,m), 1.42-1.55 (6H, m), 1.60-1.73 (3H, m), 1.75-2.10 (5H, m), 2.40-2.94(2H, m), 3.29-3.68 (10H, m), 4.15-4.36 (2H, m), 7.02-7.18 (2H, m),7.86-8.07 (1H, m).

MS (ESI+, m/e) 549 (M+1)

Reference Example 39 tert-butyl(3S,5R)-3-[{[6-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

(3R,5S)-1-(tert-Butoxycarbonyl)-5-[{[6-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid (1.05 g), HOBt (361 mg) and WSC.HCl (549 mg) were dissolved in DMF(50 ml), morpholine (332 μl) and diisopropylethylamine (780 μl) wereadded, and the mixture was stirred at 60° C. for 4 hr. The reactionmixture was cooled to room temperature, concentrated under reducedpressure, and the residue was diluted with aqueous sodium bicarbonate.The mixture was extracted with ethyl acetate, and the extract was washedwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was subjectedto silica gel column chromatography, and a fraction eluted with ethylacetate was concentrated under reduced pressure to give the objectproduct (1.14 g).

¹H-NMR (CDCl₃) δ 0.64-0.82 (3H, m), 0.89-1.05 (3H, m), 1.41-1.60 (9H,m), 1.59-1.78 (2H, m), 1.83-2.24 (3H, m), 2.28-2.99 (3H, m), 3.33 (17H,d), 3.96-4.43 (5H, m), 7.00-7.17 (2H, m), 7.49-7.75 (1H, m).

MS (ESI+, m/e) 618 (M+1)

In the same manner as in Reference Example 32, the following compound(Reference Example 40) was obtained.

Reference Example 40 4-fluoro-N-(4-methoxybutyl)-2-nitroaniline

¹H-NMR (CDCl₃) δ 1.66-1.89 (4H, m), 3.25-3.40 (5H, m), 3.44 (2H, t),6.84 (1H, dd), 7.21-7.30 (1H, m), 7.84-8.05 (2H, m).

In the same manner as in Reference Example 33, the following compound(Reference Example 41) was obtained.

Reference Example 41 5-fluoro-2-(4-methoxybutylamino)aniline

¹H-NMR (CDCl₃) δ 1.66-1.78 (4H, m), 3.12 (1H, br s), 3.04-3.11 (2H, m),3.35 (3H, s), 3.39-3.46 (2H, m), 3.58 (2H, br s), 6.42-6.51 (2H, m),6.53-6.60 (1H, m).

In the same manner as in Reference Example 34, the following compound(Reference Example 42) was obtained.

Reference Example 42 tert-butyl(3S,5R)-3-{[({5-fluoro-2-[(4-methoxybutyl)amino]phenyl}amino) (oxo)acetyl](2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 636 (M+1)

In the same manner as in Example 11, the following compound (Example 13)was obtained.

Example 135-fluoro-1-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 518 (M+1)

In the same manner as in Reference Example 35, the following compound(Reference Example 43) was obtained.

Reference Example 435-fluoro-1-(4-methoxybutyl)-2-(trichloromethyl)-1H-benzimidazole

MS (ESI+, m/e) 339 (M+1)

In the same manner as in Reference Example 37, the following compound(Reference Example 44) was obtained.

Reference Example 44 1-tert-butyl3-methyl(3R,5S)-5-[{[5-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate

MS (ESI+, m/e) 563 (M+1)

In the same manner as in Reference Example 38, the following compound(Reference Example 45) was obtained.

Reference Example 45(3R,5S)-1-(tert-butoxycarbonyl)-5-[{[5-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid

MS (ESI+, m/e) 549 (M+1)

Reference Example 46 tert-butyl(3S)-3-[(2-methylpropyl)amino]piperidine-1-carboxylate

tert-Butyl (3S)-3-aminopiperidine-1-carboxylate (5.0 g),isobutylaldehyde (2.66 ml) and acetic acid (1.72 ml) were dissolved inmethanol (100 ml), and the mixture was stirred at room temperature for10 min. Sodium triacetoxyborohydride (13.2 g) was added to the reactionmixture, and the mixture was stirred at room temperature for 30 min. Thereaction mixture was basified with aqueous sodium bicarbonate, andextracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. A part of the residue was subjectedto silica gel column chromatography, and a fraction eluted with ethylacetate-hexane (35:65) was concentrated under reduced pressure to givethe object product (3.04 g) as an oil.

¹H-NMR (CDCl₃) δ 0.79-1.15 (8H, m), 1.16-1.36 (1H, m), 1.36-1.56 (11H,m), 1.58-1.80 (2H, m), 1.80-2.00 (1H, m), 2.35-2.60 (3H, m), 2.74-2.99(1H, m), 3.68-3.91 (1H, m).

MS (ESI+, m/e) 257 (M+1)

Reference Example 47 tert-butyl(3S)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate

1-(4-Methoxybutyl)-2-(trichloromethyl)-1H-benzimidazole (470 mg) andtert-butyl (3S)-3-[(2-methylpropyl)amino]piperidine-1-carboxylate (400mg) were dissolved in acetonitrile (30 ml) and water (15 ml), potassiumcarbonate (2.02 g) was added, and the mixture was stirred at 80° C. for15 hr. The reaction mixture was cooled to room temperature and dilutedwith saturated brine. The mixture was extracted with ethyl acetate, andthe extract was washed with saturated brine and dried over anhydroussodium sulfate. The solvent was evaporated under reduced pressure. Theresidue was subjected to silica gel column chromatography, and afraction eluted with ethyl acetate-hexane (60:40) was concentrated underreduced pressure to give the object product (446 mg).

MS (ESI+, m/e) 487 (M+1)

In the same manner as in Example 12, the following compound (Example 14)was obtained.

Example 141-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S)-piperidin-3-yl]-1H-benzimidazole-2-carboxamidedihydrochloride

Reference Example 48 N-(4-methoxybutyl)-3-nitropyridin-2-amine

2-Chloro-3-nitropyridine (3.54 g) and 4-methoxybutan-1-aminehydrochloride (3.12 g) were suspended in 2-propanol (100 ml),diisopropylethylamine (11.6 μl) was added and the mixture was heatedunder reflux with stirring for 4 days. The reaction mixture was cooledto room temperature, and concentrated under reduced pressure. Theresidue was subjected to silica gel column chromatography, and afraction eluted with ethyl acetate-hexane (3:7) was concentrated underreduced pressure to give the object product (4.26 g).

¹H-NMR (CDCl₃) δ 1.63-1.85 (4H, m), 3.35 (3H, s), 3.44 (2H, t),3.61-3.72 (2H, m), 6.57-6.67 (1H, m), 8.31 (1H, br s), 8.36-8.51 (2H,m).

In the same manner as in Reference Example 33, the following compound(Reference Example 49) was obtained.

Reference Example 49 2-(4-methoxybutylamino)-3-aminopyridine

¹H-NMR (CDCl₃) δ 1.66-1.83 (4H, m), 3.36 (3H, s), 3.42-3.55 (4H, m),3.69 (2H, br s), 5.05 (1H, br s), 6.52 (1H, dd), 6.85 (1H, dd), 7.67(1H, dd).

In the same manner as in Reference Example 35, the following compound(Reference Example 50) was obtained.

Reference Example 503-(4-methoxybutyl)-2-(trichloromethyl)-3H-imidazo[4,5-b]pyridine

MS (ESI+, m/e) 322 (M+1)

In the same manner as in Reference Example 47, the following compound(Reference Example 51) was obtained.

Reference Example 51 tert-butyl(3S)-3-[{[3-(4-methoxybutyl)-3H-imidazo[4,5-b]pyridin-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate

MS (ESI+, m/e) 488 (M+1)

In the same manner as in Example 12, the following compound (Example 15)was obtained.

Example 153-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S)-piperidin-3-yl]-3H-imidazo[4,5-b]pyridine-2-carboxamidedihydrochloride

MS (ESI+, m/e) 388 (M+1)

Reference Example 521-(4-methoxybutyl)-4,5,6,7-tetrahydro-1H-benzimidazole

4,5,6,7-Tetrahydro-1H-benzimidazole (2.45 g) was dissolved in DMF (20ml), sodium hydride (60% in oil, 880 mg) was added, and the mixture wasstirred at room temperature for min. 4-Methoxybutyl methanesulfonate(1.28 g) was added, and the mixture was stirred at room temperature for15 hr. The reaction mixture was concentrated under reduced pressure,water was added and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure. The residuewas subjected to silica gel column chromatography, and a fraction elutedwith ethyl acetate was concentrated under reduced pressure to give theobject product (2.90 g).

MS (ESI+, m/e) 209 (M+1)

Reference Example 53 methyl1-(4-methoxybutyl)-4,5,6,7-tetrahydro-1H-benzimidazole-2-carboxylate

1-(4-Methoxybutyl)-4,5,6,7-tetrahydro-1H-benzimidazole (625 mg) wasdissolved in acetonitrile (5 ml), and the mixture was cooled to −15° C.Triethylamine (1.25 ml) and methyl chlorocarbonate (691 μl) were addeddropwise. The reaction mixture was heated to room temperature andstirred for 12 hr. The reaction mixture was again cooled to −15° C.,triethylamine (1.25 ml) and methyl chlorocarbonate (691 μl) were addeddropwise, heated to room temperature and stirred for 12 hr. Thisoperation was further repeated 3 times, aqueous sodium bicarbonate wasadded to the reaction mixture, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure. The residue was subjected to basic silica gel columnchromatography, and a fraction eluted with ethyl acetate wasconcentrated under reduced pressure to give the object product (225 mg).

MS (ESI+, m/e) 267 (M+1)

Reference Example 54 tert-butyl(3S,5R)-3-[{[1-(4-methoxybutyl)-4,5,6,7-tetrahydro-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

Methyl1-(4-methoxybutyl)-4,5,6,7-tetrahydro-1H-benzimidazole-2-carboxylate(225 mg) was dissolved in ethanol (10 ml) and water (5 ml), lithiumhydroxide monohydrate (53 mg) was added, and the mixture was stirred atroom temperature for 15 hr. The reaction mixture was concentrated underreduced pressure, and the residue was azeotroped with toluene. Theresidue was dissolved in 1,2-dichloroethane, tert-butyl(3S,5R)-3-[(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(314 mg), diisopropylethylamine (732 μl) andchloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (168 mg)were added, and the mixture was stirred at room temperature for 15 hr.Aqueous sodium bicarbonate was added to the reaction mixture, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure, and the residue was subjected tobasic silica gel column chromatography, and a fraction eluted with ethylacetate-hexane (6:4) was concentrated under reduced pressure to give theobject product (178 mg).

MS (ESI+, m/e) 604 (M+1)

In the same manner as in Example 12, the following compound (Example 16)was obtained.

Example 161-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-4,5,6,7-tetrahydro-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 504 (M+1)

Reference Example 55 tert-butyl(3R,5S)-3-carbamoyl-5-[{[5-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate

(3R,5S)-1-(tert-Butoxycarbonyl)-5-[{[5-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid (549 mg), 1H-1,2,3-benzotriazol-1-ol ammonium salt (304 mg) andWSC.HCl (288 mg) were dissolved in DMF (5 ml), diisopropylethylamine(517 μl) was added, and the mixture was stirred at 60° C. for 3 hr. Thereaction mixture was cooled to room temperature, concentrated underreduced pressure, and the residue was diluted with aqueous sodiumbicarbonate and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure. The residuewas subjected to silica gel column chromatography, and a fraction elutedwith ethyl acetate was concentrated under reduced pressure to give theobject product (1.14 g).

MS (ESI+, m/e) 548 (M+1)

In the same manner as in Reference Example 55, the following compound(Reference Example 56) was obtained.

Reference Example 56 tert-butyl(3R,5S)-3-carbamoyl-5-[{[6-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate

MS (ESI+, m/e) 548 (M+1)

In the same manner as in Reference Example 39, the following compounds(Reference Examples 57-59) were obtained.

Reference Example 57 tert-butyl(3S,5R)-3-[{[5-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(pyrrolidin-1-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 602 (M+1)

Reference Example 58 tert-butyl(3R,5S)-3-(azetidin-1-ylcarbonyl)-5-[{[5-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate

MS (ESI+, m/e) 558 (M+1)

Reference Example 59 tert-butyl(3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(piperidin-1-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 598 (M+1)

In the same manner as in Example 12, the following compounds (Examples17-22) were obtained.

Example 17(3R,5S)-5-[{[6-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid dihydrochloride

MS (ESI+, m/e) 449 (M+1)

Example 185-fluoro-1-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(pyrrolidin-1-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 502 (M+1)

Example 19N-[(3S,5R)-5-carbamoylpiperidin-3-yl]-5-fluoro-1-(4-methoxybutyl)-N-(2-methylpropyl)-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 448 (M+1)

Example 20N-[(3S,5R)-5-carbamoylpiperidin-3-yl]-6-fluoro-1-(4-methoxybutyl)-N-(2-methylpropyl)-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 448 (M+1)

Example 211-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(piperidin-1-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 498 (M+1)

Example 225-fluoro-1-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(4H-1,2,4-triazol-3-yl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 472 (M+1)

Example 23N-[(3S,5R)-5-(azetidin-1-ylcarbonyl)piperidin-3-yl]-5-fluoro-1-(4-methoxybutyl)-N-(2-methylpropyl)-1H-benzimidazole-2-carboxamide

tert-Butyl(3R,5S)-3-(azetidin-1-ylcarbonyl)-5-[{[5-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate(80 mg) was dissolved in trifluoroacetic acid (3 ml), and the mixturewas stirred at room temperature for 1 hr. Aqueous sodium bicarbonate wasadded to the reaction mixture, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure to give the object product (42 mg).

MS (ESI+, m/e) 488 (M+1)

Reference Example 60 tert-butyl(3S,5R)-3-[{[6-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(hydroxymethyl)piperidine-1-carboxylate

To a solution of(3R,5S)-1-(tert-butoxycarbonyl)-5-[{[6-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid (274 mg) and 4-methylmorpholine (66 μl) in THF (5 ml) was addeddropwise ethyl chlorocarbonate (57 μl) at 0° C., and the mixture wasstirred at the same temperature for 1 hr. Sodium borohydride (57 mg) andmethanol (1 ml) were added to the reaction mixture, and the mixture wasstirred at 0° C. for 1 hr. The reaction mixture was diluted with aqueoussodium bicarbonate, and the mixture was extracted with ethyl acetate.The extract was washed with saturated brine, and dried over anhydroussodium sulfate. The solvent was evaporated under reduced pressure. Theresidue was subjected to basic silica gel column chromatography, and afraction eluted with ethyl acetate was concentrated under reducedpressure to give the object product (182 mg).

MS (ESI+, m/e) 535 (M+1)

Example 246-fluoro-N-[(3S,5R)-5-(hydroxymethyl)piperidin-3-yl]-1-(4-methoxybutyl)-N-(2-methylpropyl)-1H-benzimidazole-2-carboxamidedihydrochloride

tert-Butyl(3S,5R)-3-[{[6-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(hydroxymethyl)piperidine-1-carboxylate(182 mg) was dissolved in 10-20% hydrogen chloride-methanol (5 ml), andthe mixture was stirred at room temperature for 3 days. The reactionmixture was concentrated to give the object product (169 mg).

MS (ESI+, m/e) 435 (M+1)

Reference Example 61 2-(trichloromethyl)-1H-benzimidazole

O-Phenylenediamine (25 g) was dissolved in acetic acid (750 ml), andmethyl 2,2,2-trichloroacetimidate (28.5 ml) was added dropwise over 15min. After stirring at room temperature for 1 hr, the reaction mixturewas concentrated to about 150 ml, and poured into water (1500 ml). Theprecipitated crystals were collected by filtration, washed with water(1000 ml) and suspended in toluene (500 ml). The solvent was evaporatedunder reduced pressure. The residue was again suspended in toluene (500ml) and the solvent was evaporated under reduced pressure. The residuewas dried under reduced pressure to give the object product (51.8 g).

¹H-NMR (CDCl₃) δ 7.31-7.45 (2H, m), 7.49-7.55 (1H, m), 7.89 (1H, d),9.74 (1H, br s)

In the same manner as in Reference Example 61, the following compounds(Reference Examples 62-63) were obtained.

Reference Example 62 5,6-difluoro-2-(trichloromethyl)-1H-benzimidazole

¹H-NMR (CDCl₃) δ 7.10-7.83 (2H, m), 10.10 (1H, br s)

Reference Example 63 4-chloro-2-(trichloromethyl)-1H-benzimidazole

¹H-NMR (CDCl₃) δ 7.14-7.51 (3H, m), 9.59-10.26 (1H, m)

Reference Example 64 1-tert-butyl3-methyl(3R,5S)-5-[(1H-benzimidazol-2-ylcarbonyl)(2-methylpropyl)amino]piperidine-1,3-dicarboxylate

2-(Trichloromethyl)-1H-benzimidazole (19 g) and 1-tert-butyl3-methyl(3R,5S)-5-[(2-methylpropyl)amino]piperidine-1,3-dicarboxylate(25 g) were dissolved in THF (1200 ml), sodium hydrogen carbonate (67 g)and water (600 ml) were added, and the mixture was stirred at roomtemperature for 1 hr and at 50° C. for 1 hr. After evaporation of thesolvent, the residue was extracted 3 times with ethyl acetate (700 ml).The extract was washed successively with 10%-aqueous citric acidsolution (500 ml) and brine, and dried over anhydrous sodium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in ethyl acetate (1000 ml), subjected to basic silica gelcolumn chromatography, and a fraction eluted with ethyl acetate wasconcentrated under reduced pressure to give the object product (30.6 g).

¹H-NMR (CDCl₃) δ 0.78-1.09 (6H, m), 1.17-1.55 (9H, m), 1.77-2.95 (5H,m), 3.11-3.79 (6H, m), 3.99-4.73 (4H, m), 7.24-7.41 (2H, m), 7.45-7.59(1H, m), 7.72-7.88 (1H, m), 10.66-10.98 (1H, m)

MS (ESI+, m/e) 459 (M+1)

Reference Example 65 tert-butyl(3S,5R)-3-{[(5,6-difluoro-1H-benzimidazol-2-yl)carbonyl](2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

To a solution of 5,6-difluoro-2-(trichloromethyl)-1H-benzimidazole (500mg) and tert-butyl(3S,5R)-3-[(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(680 mg) in THF (50 ml) were added sodium hydrogen carbonate (1.3 g) andwater (20 ml), and the mixture was stirred at room temperature for 1 hrand extracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. The residue was subjected to silicagel column chromatography, and a fraction eluted with ethylacetate-hexane (1:1-1:0) was concentrated under reduced pressure to givethe object product (710 mg).

MS (ESI+, m/e) 550 (M+1)

In the same manner as in Reference Example 65, the following compounds(Reference Examples 66-68) were obtained.

Reference Example 66 1-tert-butyl3-methyl(3R,5S)-5-{[(5,6-difluoro-1H-benzimidazol-2-yl)carbonyl](2-methylpropyl)amino}piperidine-1,3-dicarboxylate

MS (ESI+, m/e) 495 (M+1)

Reference Example 67 1-tert-butyl3-methyl(3R,5S)-5-{[(4-chloro-1H-benzimidazol-2-yl)carbonyl](2-methylpropyl)amino}piperidine-1,3-dicarboxylate

MS (ESI+, m/e) 493 (M+1)

Reference Example 68 1-tert-butyl 3-methyl5-[(1H-benzimidazol-2-ylcarbonyl)(2-methylpropyl)amino]piperidine-1,3-dicarboxylate

MS (ESI+, m/e) 459 (M+1)

Reference Example 69 1-tert-butyl3-methyl(3R,5S)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate

1-tert-Butyl3-methyl(3R,5S)-5-[(1H-benzimidazol-2-ylcarbonyl)(2-methylpropyl)amino]piperidine-1,3-dicarboxylate(30 g) and 4-methoxybutyl methanesulfonate (12.5 g) were dissolved inDMA (600 ml), cesium carbonate (32 g) was added, and the mixture wasstirred at 70° C. for 12 hr. The reaction mixture was poured into icewater (1000 ml), and the mixture was extracted twice with ethyl acetate(1000 ml). The extract was washed with brine, and dried over anhydroussodium sulfate. The solvent was evaporated under reduced pressure. Theresidue was subjected to silica gel column chromatography, and afraction eluted with ethyl acetate-hexane (1:4-1:1) was concentratedunder reduced pressure to give the object product (28.7 g).

¹H-NMR (CDCl₃) δ 0.76 (4H, d), 1.01 (2H, d), 1.30-1.52 (9H, m),1.58-2.07 (4H, m), 2.10-2.93 (4H, m), 3.27-3.75 (12H, m), 4.06-4.57 (5H,m), 7.26-7.48 (3H, m), 7.79 (1H, d)

MS (ESI+, m/e) 545 (M+1)

In the same manner as in Reference Example 69, the following compounds(Reference Examples 70-72) were obtained.

Reference Example 70 tert-butyl(3S,5R)-3-{[(5,6-difluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl)carbonyl](2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 636 (M+1)

Reference Example 71 1-tert-butyl3-methyl(3R,5S)-5-[{[5,6-difluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate

MS (ESI+, m/e) 495 (M+1)

Reference Example 72 1-tert-butyl 3-methyl5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-,3-dicarboxylate

MS (ESI+, m/e) 545 (M+1)

Reference Example 73 1-tert-butyl3-methyl(3R,5S)-5-[{[7-chloro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylateand 1-tert-butyl3-methyl(3R,5S)-5-[{[4-chloro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate

1-tert-Butyl3-methyl(3R,5S)-5-{[(4-chloro-1H-benzimidazol-2-yl)carbonyl](2-methylpropyl)amino}piperidine-1,3-dicarboxylate(1.7 g) and 4-methoxybutyl methanesulfonate (754 mg) were dissolved inDMA (50 ml), cesium carbonate (1.7 g) was added, and the mixture wasstirred at 70° C. for 12 hr. The reaction mixture was poured into icewater (100 ml), and the mixture was extracted twice with ethyl acetate(100 ml). The extract was washed with brine, and dried over anhydroussodium sulfate. The solvent was evaporated under reduced pressure. Theresidue was subjected to silica gel column chromatography, and a lesspolar fraction eluted with ethyl acetate-hexane (1:4-1:1) wasconcentrated under reduced is pressure to give 1-tert-butyl3-methyl(3R,5S)-5-[{[7-chloro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate(200 mg).

MS (ESI+, m/e) 580 (M+1)

A highly-polar fraction was concentrated to give 1-tert-butyl3-methyl(3R,5S)-5-[{[4-chloro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate(1.4 g).

MS (ESI+, m/e) 580 (M+1)

Reference Example 74(3R,5S)-(tert-butoxycarbonyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid

1-tert-Butyl 3-methyl(3R,5S)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate(15 g) was dissolved in methanol (150 ml), 4N-aqueous sodium hydroxidesolution (250 ml) was added, and the mixture was stirred at 50° C. for 1hr. The solvent was evaporated under reduced pressure, and the residuewas ice-cooled, neutralized with 2N hydrochloric acid, and extractedtwice ethyl acetate (500 ml). The extract was washed with brine, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure. The residue was dried under reduced pressure to givethe object product (15.0 g).

In the same manner as in Reference Example 74, the following compounds(Reference Examples 75-78) were obtained.

Reference Example 75(3R,5S)-1-(tert-butoxycarbonyl)-5-[{[5,6-difluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid

MS (ESI+, m/e) 567 (M+1)

Reference Example 76(3R,5S)-1-(tert-butoxycarbonyl)-5-[{[7-chloro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid

MS (ESI+, m/e) 565 (M+1)

Reference Example 77(3R,5S)-1-(tert-butoxycarbonyl)-5-[{[4-chloro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid

MS (ESI+, m/e) 565 (M+1)

Reference Example 781-(tert-butoxycarbonyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid

MS (ESI+, m/e) 531 (M+1)

Reference Example 79 tert-butyl(3R,5S)-3-(hydroxymethyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate

Sodium borohydride (4.45 g) was suspended in THF (25 ml)-ethanol (75ml), and calcium chloride (6.5 g) was added. After stirring at 0° C. for1 hr, a solution of 1-tert-butyl 3-methyl(3R,5S)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate(4.0 g) in THF (50 ml) was added. After stirring at room temperature for12 hr, ethyl acetate (150 ml) and water (50 ml) were slowly added inthis order, and the mixture was filtered. The organic layer of thefiltrate was partitioned, washed with brine, and dried over anhydroussodium sulfate. The solvent was evaporated under reduced pressure. Theresidue was dried under reduced pressure to give the object product (1.8g).

¹H-NMR (CDCl₃) δ 0.77 (4H, d), 1.02 (2H, d), 1.31-1.51 (9H, m),1.56-2.88 (9H, m), 3.24-3.73 (11H, m), 3.98-4.48 (5H, m), 7.28-7.53 (3H,m), 7.79 (1H, dd)

MS (ESI+, m/e) 517 (M+1)

Reference Example 80 tert-butyl(3R,5S)-3-carbamoyl-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate

A solution of(3R,5S)-1-(tert-butoxycarbonyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid (540 mg), 1H-1,2,3-benzotriazol-1-ol ammonium salt (345 mg) andWSC.HCl (383 mg) in DMF (10 ml) was stirred at room temperature for 24hr, and the mixture was poured into water and extracted with ethylacetate. The extract was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The residue was subjected to silica gel column chromatography,and a fraction eluted with ethyl acetate-hexane (1:9-1:0) wasconcentrated under reduced pressure to give the object product (270 mg).

¹H-NMR (CDCl₃) δ 0.77 (3H, d) 0.93-1.07 (3H, m), 1.21-1.55 (9H, m),1.55-3.01 (9H, m), 3.24-4.60 (12H, m), 5.45 (1H, d), 5.66-6.06 (1H, m),7.23-7.52 (3H, m), 7.79 (1H, d)

MS (ESI+, m/e) 430 (M+1)

In the same manner as in Reference Example 80, the following compound(Reference Example 81) was obtained.

Reference Example 81 tert-butyl(3R,5S)-3-carbamoyl-5-[{[5,6-difluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate

MS (ESI+, m/e) 566 (M+1)

Reference Example 82 tert-butyl(3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(pyrrolidin-1-ylcarbonyl)piperidine-1-carboxylate

(3R,5S)-1-(tert-Butoxycarbonyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid (400 mg) and pyrrolidine (59 mg) were dissolved in DMF (10 ml),WSC.HCL (217 mg) and HOBt (150 mg) were added, and the mixture wasstirred at 50° C. for 12 hr. The reaction mixture was poured into 10%aqueous sodium bicarbonate, and the mixture was extracted with ethylacetate. The extracts were combined and washed with brine and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure. The residue was subjected to silica gel column chromatography,and a fraction eluted with ethyl acetate-hexane (1:1-1:0) wasconcentrated under reduced pressure to give the object product (420 mg).

MS (ESI+, m/e) 584 (M+1)

In the same manner as in Reference Example 82, the following compounds(Reference Examples 83-91) were obtained.

Reference Example 83 tert-butyl(3RS,5RS)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 600 (M+1)

Reference Example 84 tert-butyl(3R,5S)-3-(azetidin-1-ylcarbonyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate

MS (ESI+, m/e) 570 (M+1)

Reference Example 85 tert-butyl(3R,5S)-3-[(4,4-difluoropiperidin-1-yl)carbonyl]-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate

MS (ESI+, m/e) 634 (M+1)

Reference Example 86 tert-butyl(3R,5S)-3-(7-azabicyclo[2.2.1]hepta-7-ylcarbonyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate

MS (ESI+, m/e) 610 (M+1)

Reference Example 87 tert-butyl(3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(1,4-oxazepan-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 614 (M+1)

Reference Example 88 tert-butyl(3R,5S)-3-(2,3-dihydro-4H-1,4-benzoxazin-4-ylcarbonyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate

MS (ESI+, m/e) 648 (M+1)

Reference Example 89 tert-butyl(3R,5S)-3-(azetidin-1-ylcarbonyl)-5-[{[5,6-difluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate

MS (ESI+, m/e) 606 (M+1)

Reference Example 90 tert-butyl(3S,5R)-3-[{[7-chloro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 634 (M+1)

Reference Example 91 tert-butyl(3S,5R)-3-[{[4-chloro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 634 (M+1)

Reference Example 92 tert-butyl(3R,5S)-3-(1-hydroxy-1-methylethyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate

A solution of 1-tert-butyl3-methyl(3R,5S)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate(330 mg) in THF (5 ml) was cooled to −40° C., a solution (1 ml) of3M-methyl magnesium bromide in ether was added and the mixture wasstirred at room temperature for 1 hr. The reaction mixture was pouredinto saturated aqueous ammonium chloride solution, and the mixture wasextracted with ethyl acetate. The extract was dried over anhydroussodium sulfate and the solvent was evaporated under reduced pressure.The residue was subjected to silica gel column chromatography, and afraction eluted with ethyl acetate-hexane (1:1-1:0) was concentratedunder reduced pressure to give the object product (180 mg).

MS (ESI+, m/e) 545 (M+1)

In the same manner as in Reference Example 92, the following compound(Reference Example 93) was obtained.

Reference Example 93 tert-butyl(3S,5R)-3-[{[5,6-difluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(1-hydroxy-1-methylethyl)piperidine-1-carboxylate

MS (ESI+, m/e) 581 (M+1)

Reference Example 94 tert-butyl(3R,5S)-3-formyl-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate

To a solution of tert-butyl(3R,5S)-3-(hydroxymethyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate(1.0 g) in acetonitrile (20 ml) was added1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (0.98 g),and the mixture was stirred at room temperature for 3 hr. 10% Aqueoussodium thiosulfate solution was added to the reaction mixture, and themixture was stirred for 30 min. After partitioning, the organic layerwas washed with saturated aqueous sodium hydrogen carbonate and brine,and dried over anhydrous sodium sulfate. The solvent was evaporatedunder reduced pressure. The residue was subjected to silica gel columnchromatography, and a fraction eluted with ethyl acetate-hexane (1:1)was concentrated under reduced pressure to give the object product (1.0g).

MS (ESI+, m/e) 515 (M+1)

Reference Example 95 tert-butyl(3R,5S)-3-(1-hydroxyethyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate

To a solution of tert-butyl(3R,5S)-3-formyl-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate(150 mg) in THF (10 ml) was added 3M-methyl magnesium bromide-ethersolution (0.3 ml), and the mixture was stirred at room temperature for 1hr. The reaction mixture was poured into saturated aqueous ammoniumchloride solution, and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure. The residuewas subjected to silica gel column chromatography, and a fraction elutedwith ethyl acetate-hexane (1:1-1:0) was concentrated under reducedpressure to give the object product (100 mg).

MS (ESI+, m/e) 531 (M+1)

In the same manner as in Reference Example 95, the following compound(Reference Example 96) was obtained.

Reference Example 96 tert-butyl(3R,5S)-3-[cyclopropyl(hydroxy)methyl]-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate

MS (ESI+, m/e) 557 (M+1)

Reference Example 97 tert-butyl(3R,5S)-3-[hydroxy(pyridin-2-yl)methyl]-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl)carbonyl)(2-methylpropyl)amino)piperidine-1-carboxylate

To a solution of bromopyridine (0.058 ml) cooled to −78° C. in THF (5ml) was added 1.6M-butyllithium hexane solution (0.33 ml) and themixture was stirred for 30 min. A solution of tert-butyl(3R,5S)-3-formyl-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate(257 mg) in THF (5 ml) was added and the mixture was stirred at −20° C.for 2 hr. The reaction mixture was poured into saturated aqueousammonium chloride solution, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure. The residue was subjected to silica gel column chromatography,and a fraction eluted with ethyl acetate-hexane (1:1-1:0) wasconcentrated under reduced pressure to give the object product (100 mg).

MS (ESI+, m/e) 594 (M+1)

Reference Example 98 tert-butyl(3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(oxiran-2-yl)piperidine-1-carboxylate

Trimethylsulfoxonium iodide (240 mg) was dissolved in DMSO (5 ml),sodium hydride (60% in oil, 45 mg) was added, and the mixture wasstirred at room temperature for 30 min. A solution of tert-butyl(3R,5S)-3-formyl-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate(450 mg) in DMSO (10 ml) was added and the mixture was stirred at roomtemperature for 30 min. The reaction mixture was poured into saturatedaqueous ammonium chloride solution and the mixture was extracted withethyl acetate. The extract was dried over anhydrous sodium sulfate andthe solvent was evaporated under reduced pressure. The residue wassubjected to silica gel column chromatography, and a fraction elutedwith ethyl acetate was concentrated under reduced pressure to give theobject product (230 mg).

MS (ESI+, m/e) 529 (M+1)

Reference Example 99 tert-butyl(3R,5S)-3-(1-hydroxy-2-methoxyethyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate

tert-Butyl(3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-oxirane-2-ylpiperidine-1-carboxylate(200 mg) was dissolved in methanol (5 ml), 28% sodium methylate-methanolsolution was added, and the mixture was stirred at 70° C. for 6 hr. Thesolvent was evaporated under reduced pressure, and the residue wasextracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. The residue was subjected to silicagel column chromatography, and a fraction eluted with ethylacetate-hexane (1:1-1:0) was concentrated under reduced pressure to givethe object product (157 mg).

MS (ESI+, m/e) 561 (M+1)

Reference Example 100 tert-butyl(3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(5-methyl-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate

Methyltetrazole (63 mg) and(3R,5S)-1-(tert-butoxycarbonyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid (265 mg) were dissolved in toluene (5 ml), DCC (155 mg) was addedand the mixture was stirred at 100° C. for 12 hr. The reaction mixturewas diluted with ethyl acetate, filtered and the solvent of the motherliquor was evaporated under reduced pressure. The residue was subjectedto silica gel column chromatography, and a fraction eluted with ethylacetate-hexane (1:1-1:0) was concentrated under reduced pressure to givethe object product (100 mg).

MS (ESI+, m/e) 569 (M+1)

Example 25N-[(3S,5R)-5-carbamoylpiperidin-3-yl]-1-(4-methoxybutyl)-N-(2-methylpropyl)-1H-benzimidazole-2-carboxamidedihydrochloride

tert-Butyl(3R,5S)-3-carbamoyl-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate(260 mg) was dissolved in ethyl acetate (3 ml), 4N hydrogenchloride-ethyl acetate (5 ml) was added, and the mixture was stirred for1 hr. The solvent was evaporated under reduced pressure to give theobject product (220 mg).

¹H-NMR (DMSO-d₆) δ 0.61-0.79 (3H, m) 0.88-0.99 (3H, m), 1.45-1.60 (2H,m), 1.74-1.88 (2H, m), 2.07-2.41 (2H, m), 2.70-3.01 (1H, m), 3.10-3.63(9H, m), 4.21-4.41 (3H, m), 7.12 (1H, br s), 7.28-7.48 (2H, m),7.53-7.84 (3H, m), 8.98 (2H, br s), 9.54-9.95 (2H, m)

MS (ESI+, m/e) 430 (M+1)

In the same manner as in Example 25, the following compounds (Examples26-39) were obtained.

Example 26 1-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3RS,5RS)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidedihydrochloride

Example 271-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(pyrrolidin-1-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 484 (M+1)

Example 28N-{(3S,5R)-5-[(4,4-difluoropiperidin-1-yl)carbonyl]piperidin-3-yl}-1-(4-methoxybutyl)-N-(2-methylpropyl)-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 534 (M+1)

Example 29N-[(3S,5R)-5-(7-azabicyclo[2.2.1]hept-7-ylcarbonyl)piperidin-3-yl]-1-(4-methoxybutyl)-N-(2-methylpropyl)-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 510 (M+1)

Example 301-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(1,4-oxazepan-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 514 (M+1)

Example 31N-[(3S,5R)-5-(2,3-dihydro-4H-1,4-benzoxazin-4-ylcarbonyl)piperidin-3-yl]-(4-methoxybutyl)-N-(2-methylpropyl)-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 548 (M+1)

Example 32methyl(3R,5S)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylatedihydrochloride

MS (ESI+, m/e) 445 (M+1)

Example 33(3R,5S)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid dihydrochloride

MS (ESI+, m/e) 431 (M+1)

Example 345,6-difluoro-1-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 536 (M+1)

Example 35N-[(3S,5R)-5-carbamoylpiperidin-3-yl]-5,6-difluoro-(4-methoxybutyl)-N-(2-methylpropyl)-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 466 (M+1)

Example 367-chloro-1-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 534 (M+1)

Example 374-chloro-1-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 534 (M+1)

Example 38N-[(3S,5R)-5-(1-hydroxy-1-methylethyl)piperidin-3-yl]-1-(4-methoxybutyl)-N-(2-methylpropyl)-1H-benzimidazole-2-carboxamidedihydrochloride

tert-Butyl(3R,5S)-3-(1-hydroxy-1-methylethyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate(180 mg) was dissolved in ethyl acetate (2 ml), 4N hydrogenchloride-ethyl acetate (4 ml) was added, and the mixture was stirred for1 hr. The solvent was evaporated under reduced pressure to give theobject product (130 mg).

¹H-NMR (DMSO-d₆) δ 0.64-0.75 (2H, m), 0.86-0.98 (4H, m), 1.40-1.58 (2H,m), 1.65-1.88 (2H, m), 1.88-2.36 (4H, m), 2.69-3.63 (9H, m), 3.79-3.95(3H, m), 4.07-4.40 (5H, m), 4.99 (2H, br s), 7.22-7.44 (2H, m),7.62-7.79 (2H, m), 8.41 (1H, br s), 8.67-8.87 (1H, m), 9.14 (1H, br s)

MS (ESI+, m/e) 445 (M+1)

Example 395,6-difluoro-N-[(3S,5R)-5-(1-hydroxy-1-methylethyl)piperidin-3-yl]-1-(4-methoxybutyl)-N-(2-methylpropyl)-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 481 (M+1)

Example 40N-[(3S,5R)-5-(hydroxymethyl)piperidin-3-yl]-(4-methoxybutyl)-N-(2-methylpropyl)-1H-benzimidazole-2-carboxamidedihydrochloride

To tert-butyl(3R,5S)-3-(hydroxymethyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate(150 mg) in THF (2 ml) was added TFA (5 ml) and the mixture was stirredat room temperature for 1 hr. The solvent was evaporated under reducedpressure, and the residue was subjected to reversed-phase preparativeHPLC and the eluted fraction was concentrated under reduced pressure.The residual aqueous layer was neutralized with saturated aqueous sodiumhydrogen carbonate and extracted with ethyl acetate. The extract wasdried over anhydrous sodium sulfate, 10-20% hydrogen chloride-methanolwas added, and the solvent was evaporated under reduced pressure to givethe object product (75 mg).

¹H-NMR (DMSO-d₆) δ 0.67-0.76 (3H, m) 0.90-0.99 (3H, m), 1.37-1.58 (2H,m), 1.63-1.88 (2H, m), 1.86-2.21 (2H, m), 2.50 (2H, dt), 3.02-4.92 (16H,m), 7.37 (2H, d), 7.63-7.84 (2H, m), 8.65 (1H, br s), 9.05-9.74 (1H, m)

MS (ESI+, m/e) 417 (M+1)

In the same manner as in Example 40, the following compounds (Examples41-44) were obtained.

Example 411-(4-methoxybutyl)-N-[(3S,5R)-5-(5-methyl-1,3,4-oxadiazol-2-yl)piperidin-3-yl]-N-(2-methylpropyl)-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 469 (M+1)

Example 42N-[(3S,5R)-5-(1-hydroxyethyl)piperidin-3-yl]-(4-methoxybutyl)-N-(2-methylpropyl)-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 431 (M+1)

Example 43N-{(3S,5R)-5-[cyclopropyl(hydroxy)methyl]piperidin-3-yl}-1-(4-methoxybutyl)-N-(2-methylpropyl)-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 457 (M+1)

Example 44N-{(3S,5R)-5-[hydroxy(pyridin-2-yl)methyl]piperidin-3-yl}-1-(4-methoxybutyl)-N-(2-methylpropyl)-1H-benzimidazole-2-carboxamidetrihydrochloride

MS (ESI+, m/e) 494 (M+1)

Example 45N-[(3S,5R)-5-(azetidin-1-ylcarbonyl)piperidin-3-yl]-1-(4-methoxybutyl)-N-(2-methylpropyl)-1H-benzimidazole-2-carboxamide

To tert-butyl(3R,5S)-3-(azetidin-1-ylcarbonyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate(230 mg) in 1,2-dichloroethane (3 ml) was added TFA (3 ml) and themixture was stirred at room temperature for 1 hr. The solvent wasevaporated under reduced pressure, and the residue was dissolved inethyl acetate-water, and neutralized with saturated aqueous sodiumhydrogen carbonate. The organic layer was dried over anhydrous sodiumsulfate and the solvent was evaporated under reduced pressure to givethe object product (100 mg).

MS (ESI+, m/e) 470 (M+1)

Example 46N-[(3S,5R)-5-(azetidin-1-ylcarbonyl)piperidin-3-yl]-5,6-difluoro-1-(4-methoxybutyl)-N-(2-methylpropyl)-1H-benzimidazole-2-carboxamide½ fumarate

To tert-butyl(3R,5S)-3-(azetidin-1-ylcarbonyl)-5-[{[5,6-difluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate(270 mg) in 1,2-dichloroethane (3 ml) was added TFA (5 ml) and themixture was stirred at room temperature for 1 hr. The solvent wasevaporated under reduced pressure, and the residue was dissolved inethyl acetate-water, and neutralized with saturated aqueous sodiumhydrogen carbonate. The organic layer was dried over anhydrous sodiumsulfate, fumaric acid (23 mg) was added, and the solvent was evaporatedunder reduced pressure to give the object product (210 mg).

MS (ESI+, m/e) 506 (M+1)

Example 47{(3R,5S)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidin-3-yl}methylacetate dihydrochloride

tert-Butyl(3R,5S)-3-(hydroxymethyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate(200 mg) was dissolved in ethyl acetate (2 ml), 4N hydrogenchloride-ethyl acetate (5 ml) was added, and the mixture was stirred for1 hr. The solvent was evaporated under reduced pressure to give theobject product (200 mg).

MS (ESI+, m/e) 459 (M+1)

Example 48N-[(3S,5R)-5-(1-hydroxy-2-methoxyethyl)piperidin-3-yl]-1-(4-methoxybutyl)-N-(2-methylpropyl)-1H-benzimidazole-2-carboxamidedihydrochloride

tert-Butyl(5S)-3-(1-hydroxy-2-methoxyethyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate(150 mg) was dissolved in 10-20%-hydrogen chloride methanol solution (10ml), and the mixture was stirred at room temperature for 3 hr. Thesolvent was evaporated under reduced pressure to give the object product(140 mg).

MS (ESI+, m/e) 461 (M+1)

Example 491-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidemethanesulfonate

tert-Butyl(3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(10.2 g) was dissolved in ethyl acetate (17 ml) and methanol (5 ml), 4Nhydrogen chloride-ethyl acetate (34 ml) was added, and the mixture wasstirred for 1 hr. The reaction mixture was poured into 10%-aqueoussodium hydrogen carbonate solution (125 ml), and the mixture wasextracted with ethyl acetate. The extract was washed with brine, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure. A part (7.8 g) of the residue (8.1 g) was dissolved inethyl acetate (60 ml), and dissolved in methanesulfonic acid (1.5 g) byheating (90° C.). This was stood at room temperature for 4 days, and theprecipitated crystals were collected by filtration to give the objectproduct as crude crystals (7.3 g).

MS (ESI+, m/e) 500 (M+1)

Reference Example 101 2-fluoro-N-(4-methoxybutyl)-6-nitroaniline

To a solution of 1,2-difluoro-3-nitrobenzene (5.15 g) and4-methoxybutan-1-amine hydrochloride (5.42 g) in acetonitrile (100 ml)was added diisopropylethylamine (17 μl), and the mixture was stirred at60° C. for 12 hr. 4-Methoxybutan-1-amine hydrochloride (1.00 g) wasfurther added, and the mixture was stirred at 70° C. for 5 hr. Thereaction mixture was concentrated under reduced pressure, saturatedaqueous sodium hydrogen carbonate was added, and the mixture wasextracted with ethyl acetate. The extract was dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas subjected to silica gel column chromatography, and a fraction elutedwith hexane-ethyl acetate-hexane (3:7) was concentrated under reducedpressure to give the object product (7.70 g).

¹H-NMR (CDCl₃) δ 1.62-1.82 (4H, m), 3.34 (3H, s), 3.42 (2H, t), 3.61(2H, ddd), 6.56 (1H, ddd), 7.17 (1H, ddd), 7.85 (1H, br s), 7.95 (1H,dt)

Reference Example 102 3-fluoro-2-(4-methoxybutylamino)aniline

2-Fluoro-N-(4-methoxybutyl)-6-nitroaniline (3.54 g) was dissolved inmethanol (50 ml), palladium-carbon (5%, 140 mg) was added, and themixture was stirred for 3.5 hr under a hydrogen atmosphere. The reactionmixture was filtered through celite, and the filtrate was concentratedunder reduced pressure to give the object product (3.05 g).

¹H-NMR (CDCl₃) δ 1.49-1.76 (4H, m), 2.89-3.12 (1H, m), 2.98 (2H, t),3.34 (3H, s), 3.40 (2H, t), 3.91 (2H, br s), 6.43-6.52 (2H, m), 6.78(1H, td)

Reference Example 103(3R,5S)-1-(tert-butoxycarbonyl)-5-[{[7-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid

3-Fluoro-2-(4-methoxybutylamino)aniline (3.05 g) was dissolved in aceticacid (80 ml), methyl 2,2,2-trichloroethanimidate (1.92 ml) was added,and the mixture was stirred for 1.5 hr. The reaction mixture wasconcentrated under reduced pressure, and the residue was diluted withdiisopropyl ether, and washed with water. The organic layer was driedover anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was immediately dissolved in acetonitrile-water(2:1, 225 ml), and 1-tert-butyl 3-methyl(3R,5S)-5-{(2-methylpropyl)amino}piperidine-1,3-dicarboxylate (3.58 g)was added. Potassium carbonate (16 g) was added, and the mixture wasstirred at 80° C. for 19 hr. The reaction mixture was concentrated underreduced pressure, diluted with saturated aqueous ammonium chloridesolution, and the mixture was extracted with ethyl acetate. The extractwas dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The residue was subjected to silica gelchromatography, and a fraction eluted with ethyl acetate-hexane(5:95)-ethyl acetate-ethyl acetate-methanol (85:15) was concentratedunder reduced pressure to give the object product (1.65 g).

MS (ESI+, m/e) 549 (M+1)

Reference Example 104 tert-butyl(3S,5R)-3-{{{7-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

(3R,5S)-1-(tert-Butoxycarbonyl)-5-[{[7-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid (207 mg), morpholine (87 μl), HOBt (40 mg) and triethylamine (210μl) were dissolved in DMF (10 ml), WSC.HCl (180 mg) was added, and themixture was stirred at 50° C. for 1 hr. The reaction mixture wasconcentrated under reduced pressure, diluted with saturated aqueoussodium hydrogen carbonate, and the mixture was extracted with ethylacetate. The extract was dried over anhydrous magnesium sulfate and thesolvent was evaporated under reduced pressure. The residue was subjectedto silica gel column chromatography, and a fraction eluted with ethylacetate-hexane (1:9)-ethyl acetate was concentrated under reducedpressure to give the object product (160 mg).

MS (ESI+, m/e) 618 (M+1)

Reference Example 105 tert-butyl(3R,5S)-3-carbamoyl-5-{{{7-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}piperidine-1-carboxylate

(3R,5S)-1-(tert-Butoxycarbonyl)-5-[{[7-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid (360 mg), 1H-1,2,3-benzotriazol-1-ol ammonium salt (250 mg) andtriethylamine (360 μl) were dissolved in DMF (10 ml), WSC.HCl (315 mg)was added, and the mixture was stirred at 50° C. for 1 hr. The reactionmixture was concentrated under reduced pressure, diluted with saturatedaqueous sodium hydrogen carbonate, and the mixture was extracted withethyl acetate. The extract was dried over anhydrous magnesium sulfateand the solvent was evaporated under reduced pressure. The residue wassubjected to silica gel column chromatography, and a fraction elutedwith ethyl acetate-hexane (3:7)-ethyl acetate-ethyl acetate-methanol(9:1) was concentrated under reduced pressure to give the object product(263 mg).

MS (ESI+, m/e) 548 (M+1)

Reference Example 106 tert-butyl(3S,5R)-3-{{{7-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}-5-(4H-1,2,4-triazol-3-yl)piperidine-1-carboxylate

tert-Butyl(3R,5S)-3-carbamoyl-5-{{{7-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}piperidine-1-carboxylate(115 mg) was dissolved in dimethylformamide dimethylacetal (5 ml), andthe mixture was stirred at 100° C. for 15 hr. The reaction mixture wasconcentrated under reduced pressure, and the residue was dissolved inacetic acid (7 ml). Hydrazine monohydrate (48 μl) was added and themixture was stirred at 80° C. for 3 hr. The reaction mixture wasconcentrated under reduced pressure, diluted with 0.5M aqueous sodiumhydroxide solution, and the mixture was extracted with ethyl acetate.The extract was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The residue was subjected to silica gel column chromatography, and afraction eluted with ethyl acetate-ethyl acetate-methanol (9:1) wasconcentrated under reduced pressure to give the object product (130 mg).

MS (ESI+, m/e) 572 (M+1)

Reference Example 107 tert-butyl(3S,5R)-3-{{{7-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}-5-(pyrrolidin-1-ylcarbonyl)piperidine-1-carboxylate

(3R,5S)-1-(tert-Butoxycarbonyl)-5-[{[7-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid (1.65 g), pyrrolidine (5001), HOBt (270 mg) and triethylamine (1.27ml) were dissolved in DMF (50 ml), WSC.HCl (1.15 g) was added, and themixture was stirred at 50° C. for 1 hr. The reaction mixture wasconcentrated under reduced pressure, diluted with saturated aqueoussodium hydrogen carbonate, and the mixture was extracted with ethylacetate. The extract was dried over anhydrous magnesium sulfate and thesolvent was evaporated under reduced pressure. The residue was subjectedto silica gel column chromatography, and a fraction eluted with ethylacetate-hexane (5:95)-ethyl acetate-ethyl acetate-methanol (9:1) wasconcentrated under reduced pressure to give the object product (170 mg).

MS (ESI+, m/e) 602 (M+1)

Example 507-fluoro-1-(4-methoxybutyl)-N-(2-methylpropyl)-N-{(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl}-1H-benzimidazole-2-carboxamidedihydrochloride

tert-Butyl(3S,5R)-3-{{{7-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(160 mg) was dissolved in 2M hydrogen chloride-ethyl acetate (3 ml), andthe mixture was stirred at room temperature for 10 hr. The reactionmixture was concentrated under reduced pressure. The residue wassubjected to reversed-phase preparative HPLC, and a fraction eluted withwater-acetonitrile (9:1-6:4) was collected, basified (pH 10) withsaturated aqueous potassium carbonate solution, and extracted with ethylacetate. The extract was dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was dissolved in 1Mhydrogen chloride-ethyl acetate (1 ml), and the reaction mixture wasconcentrated under reduced pressure to give the object product (104 mg).

MS (ESI+, m/e) 518 (M+1)

In the same manner as in Example 50, the following compounds (Examples51-52) were obtained.

Example 51N-{(3S,5R)-5-carbamoylpiperidin-3-yl}-7-fluoro-1-(4-methoxybutyl)-N-(2-methylpropyl)-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 448 (M+1)

Example 527-fluoro-1-(4-methoxybutyl)-N-(2-methylpropyl)-N-{(3S,5R)-5-(pyrrolidin-1-ylcarbonyl)piperidin-3-yl}-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 502 (M+1)

Example 537-fluoro-1-(4-methoxybutyl)-N-(2-methylpropyl)-N-{(3S,5R)-5-(4H-1,2,4-triazol-3-yl)piperidin-3-yl}-1H-benzimidazole-2-carboxamidedihydrochloride

tert-Butyl(3S,5R)-3-{{{7-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}-5-(4H-1,2,4-triazol-3-yl)piperidine-1-carboxylate(130 mg) was dissolved in 2M hydrogen chloride-ethyl acetate (3 ml), andthe mixture was stirred at room temperature for 12 hr. The reactionmixture was concentrated to give the object product (91 mg).

MS (ESI+, m/e) 472 (M+1)

Reference Example 108 3-fluoro-N-(4-methoxybutyl)-2-nitroaniline

To a solution of 1,3-difluoro-2-nitrobenzene (3.00 g) anddiisopropylethylamine (7 μl) in acetonitrile (30 ml) was added asolution of 4-methoxybutan-1-amine hydrochloride (2.51 g) inacetonitrile (10 ml), and the mixture was stirred at room temperaturefor 90 hr. The reaction mixture was concentrated under reduced pressure,and the residue was subjected to silica gel column chromatography, and afraction eluted with ethyl acetate-hexane (2:98-25:75) was concentratedunder reduced pressure to give the object product (2.90 g).

¹H-NMR (CDCl₃) δ 1.65-1.84 (4H, m), 3.28 (2H, ddd), 3.35 (3H, s), 3.43(2H, t), 6.41 (1H, ddd), 6.58 (1H, d), 7.22-7.32 (2H, m)

Reference Example 109 6-fluoro-2-(4-methoxybutylamino)aniline

3-Fluoro-N-(4-methoxybutyl)-2-nitroaniline (2.90 g) was dissolved inmethanol (50 ml), palladium-carbon (5%, 230 mg) was added, and themixture was stirred for 3 hr under a hydrogen atmosphere. The reactionmixture was filtered through celite, and the filtrate was concentratedunder reduced pressure to give the object product (2.54 g).

¹H-NMR (CDCl₃) δ 1.64-1.79 (4H, m), 3.14 (2H, t), 3.18-3.32 (2H, m),3.35 (3H, s), 3.43 (2H, t), 3.53 (1H, br s), 6.42 (1H, d), 6.51 (1H,ddd), 6.73 (1H, td)

Reference Example 110 1-tert-butyl3-methyl(3R,5S)-5-{{{4-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}piperidine-1,3-dicarboxylate

6-Fluoro-2-(4-methoxybutylamino)aniline (2.54 g) was dissolved in aceticacid (90 ml), methyl 2,2,2-trichloroethanimidate (1.48 ml) was added,and the mixture was stirred for 1.5 hr. The reaction mixture wasconcentrated under reduced pressure, and the residue was suspended intoluene (50 ml) and concentrated under reduced pressure. This operationwas repeated twice. The residue was immediately dissolved inacetonitrile-water (3:1, 200 ml), 1-tert-butyl3-methyl(3R,5S)-5-{(2-methylpropyl)amino}piperidine-1,3-dicarboxylate(3.70 g) was added, and potassium carbonate (16.5 g) was added and themixture was stirred at 80° C. for 19 hr. The reaction mixture wasconcentrated under reduced pressure, diluted with saturated aqueousammonium chloride solution, and extracted with ethyl acetate. Theextract was dried over anhydrous magnesium sulfate, and concentratedunder reduced pressure. The residue was subjected to silica gelchromatography, and a fraction eluted with ethyl acetate-hexane(5:95-1:1) was concentrated under reduced pressure to give the objectproduct (195 mg).

MS (ESI+, m/e) 563 (M+1)

Reference Example 111(3R,5S)-1-(tert-butoxycarbonyl)-5-{{{4-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}piperidine-3-carboxylicacid

1-tert-Butyl3-methyl(3R,5S)-5-{{{4-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}piperidine-1,3-dicarboxylate(195 mg) was dissolved in tetrahydrofuran-methanol (1:2, 15 ml), 2Maqueous sodium hydroxide solution (1 ml) was added, and the mixture wasstirred at 45° C. for 4 hr. The reaction mixture was concentrated underreduced pressure, neutralized with saturated aqueous ammonium chloridesolution and extracted with ethyl acetate. The extract was dried overanhydrous magnesium sulfate, concentration under reduced pressure togive the object product (180 mg).

MS (ESI+, m/e) 549 (M+1)

In the same manner as in Reference Example 104, the following compound(Reference Example 112) was obtained.

Reference Example 112 tert-butyl(3S,5R)-3-{{{4-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 618 (M+1)

Example 544-fluoro-1-(4-methoxybutyl)-N-(2-methylpropyl)-N-{(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl}-1H-benzimidazole-2-carboxamidedihydrochloride

tert-Butyl(3S,5R)-3-{{{4-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(75 mg) was dissolved in 3M hydrogen chloride-ethyl acetate (2 ml), andthe mixture was stirred at room temperature for 30 min and concentratedto give the object product (67 mg).

MS (ESI+, m/e) 518-(M+1)

Reference Example 113 tert-butyl (3-methoxy-2-nitrophenyl)carbamate

3-Methoxy-2-nitrobenzoic acid (10.25 g) was suspended in toluene (200ml), and triethylamine (8.65 ml) and diphenylphosphoryl azide (13.4 ml)were added dropwise at room temperature. The mixture was stirred at 90°C. for 1.5 hr, triethylamine (29 ml) and 2-methylpropan-2-ol (15 ml)were added, and the mixture was further stirred at 90° C. for 2 hr. Thereaction mixture was concentrated under reduced pressure, diluted withethyl acetate, 0.5M hydrochloric acid (200 ml) was added, and themixture was filtered through celite. The organic layer of the filtratewas collected, washed with saturated aqueous sodium hydrogen carbonate,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was subjected to silica gel chromatography, and afraction eluted with ethyl acetate-hexane (5:95-1:1) was concentratedunder reduced pressure to give the object product (10.18 g).

¹H-NMR (CDCl₃) δ 1.50 (8H, s), 3.90 (3H, s), 6.71 (1H, d), 7.39 (2H, t),7.55 (1H, br s), 7.77 (1H, d)

Reference Example 114 tert-butyl(4-methoxybutyl)(3-methoxy-2-nitrophenyl)carbamate

tert-Butyl (3-methoxy-2-nitrophenyl)carbamate (3.00 g) and4-methoxybutyl methanesulfonate (3.06 g) were dissolved indimethylformamide (40 ml), cesium carbonate (7.30 g) was added, and themixture was stirred at 65° C. for 4 hr. The reaction mixture wasconcentrated under reduced pressure, diluted with water, and the mixturewas extracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was subjected to silica gelchromatography, and a fraction eluted with ethyl acetate-hexane(5:95-7:3) was concentrated under reduced pressure to give the objectproduct (2.11 g).

¹H-NMR (CDCl₃) δ 1.36 (9H, br s), 1.47-1.71 (6H, m), 3.30 (3H, s), 3.37(2H, t), 3.91 (3H, s), 6.86 (1H, d), 6.98 (1H, d), 7.40 (1H, t)

Reference Example 115 3-methoxy-N-(4-methoxybutyl)-2-nitroaniline

tert-Butyl (4-methoxybutyl) (3-methoxy-2-nitrophenyl)carbamate (2.11 g)was dissolved in ethyl acetate (30 ml), 4M hydrogen chloride-ethylacetate (15 ml) was added, and the mixture was stirred for 12 hr. Thereaction mixture was concentrated under reduced pressure, diluted withsaturated aqueous sodium hydrogen carbonate, and the mixture wasextracted with ethyl acetate. The extract was dried over anhydrousmagnesium sulfate, concentration under reduced pressure to give theobject product (1.50 g).

¹H-NMR (CDCl₃) δ 1.60-1.80 (4H, m), 3.21 (2H, ddd), 3.34 (3H, s), 3.41(2H, t), 3.87 (3H, s), 6.17 (1H, br s), 6.25 (1H, d), 6.37 (1H, d), 7.22(1H, t)

Reference Example 116 6-methoxy-2-(4-methoxybutylamino)aniline

3-Methoxy-N-(4-methoxybutyl)-2-nitroaniline (230 mg) was dissolved inmethanol (30 ml), palladium-carbon (5%, 90 mg) was added, and themixture was stirred for 2 hr under a hydrogen atmosphere. The reactionmixture was filtered through celite, and the filtrate was concentratedunder reduced pressure to give the object product (210 mg).

¹H-NMR (CDCl₃) δ 1.67-1.78 (4H, m), 3.10-3.20 (2H, m), 3.31-3.47 (5H,m), 3.35 (3H, s), 3.84 (3H, s), 6.37 (1H, dd), 6.40 (1H, dd), 6.77 (1H,t)

Reference Example 117 tert-butyl(3S,5R)-3-{{({2-methoxy-6-{(4-methoxybutyl)amino}phenyl}amino)(oxo)acetyl}(2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

6-Methoxy-2-(4-methoxybutylamino)aniline (210 mg),{{(3S,5R)-1-(tert-butoxycarbonyl)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl}(2-methylpropyl)amino}(oxo)aceticacid (308 mg), HOBt (97 mg) and triethylamine (3701) were dissolved in1,2-dichloroethane (15 ml), WSC.HCl (430 mg) was added, and the mixturewas stirred at 60° C. for 2 hr. The reaction mixture was concentratedunder reduced pressure, diluted with saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The extractwas dried over anhydrous magnesium sulfate and the solvent wasevaporated under reduced pressure. The residue was subjected to silicagel column chromatography, and a fraction eluted with ethylacetate-hexane (2:8)-ethyl acetate was concentrated under reducedpressure to give the object product (240 mg).

MS (ESI+, m/e) 648 (M+1)

In the same manner as in Reference Example 103, the following compound(Reference Example 118) was obtained.

Reference Example 118(3R,5S)-1-(tert-butoxycarbonyl)-5-{{{4-methoxy-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}piperidine-3-carboxylicacid

MS (ESI+, m/e) 561 (M+1)

In the same manner as in Reference Example 105, the following compound(Reference Example 119) was obtained.

Reference Example 119 tert-butyl(3R,5S)-3-carbamoyl-5-{{{4-methoxy-1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}piperidine-1-carboxylate

MS (ESI+, m/e) 560 (M+1)

In the same manner as in Reference Example 106, the following compound(Reference Example 120) was obtained.

Reference Example 120 tert-butyl(3S,5R)-3-{{{4-methoxy-1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}-5-(4H-1,2,4-triazol-3-yl)piperidine-1-carboxylate

MS (ESI+, m/e) 584 (M+1)

In the same manner as in Reference Example 107, the following compound(Reference Example 121) was obtained.

Reference Example 121 tert-butyl(3S,5R)-3-{{{4-methoxy-1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}-5-(pyrrolidin-1-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 614 (M+1)

Reference Example 122 tert-butyl(3S,5R)-3-{{{4-methoxy-1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}-5-(piperidin-1-ylcarbonyl)piperidine-1-carboxylate

(3R,5S)-1-(tert-Butoxycarbonyl)-5-{{{4-methoxy-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}piperidine-3-carboxylicacid (205 mg), piperidine (69 μl), HOBt (40 mg) and triethylamine (140μl) were dissolved in DMF (10 ml), WSC.HCl (134 mg) was added, and themixture was stirred at 50° C. for 1 hr. The reaction mixture wasconcentrated under reduced pressure, diluted with saturated aqueoussodium hydrogen carbonate, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The residue was subjected to silica gel column chromatography,and a fraction eluted with ethyl acetate-hexane (1:9)-ethyl acetate wasconcentrated under reduced pressure to give the object product (65 mg).

MS (ESI+, m/e) 628 (M+1)

Example 554-methoxy-1-(4-methoxybutyl)-N-(2-methylpropyl)-N-{(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl}-1H-benzimidazole-2-carboxamidedihydrochloride

tert-Butyl(3S,5R)-3-{{({2-methoxy-6-{(4-methoxybutyl)amino}phenyl}amino)(oxo)acetyl}(2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(240 mg) was dissolved in acetic acid (5 ml), and the mixture wasstirred at 80° C. for 14 hr. The reaction mixture was concentrated underreduced pressure, the residue was dissolved in 2M hydrogenchloride-ethyl acetate (3 ml), and the mixture was stirred at roomtemperature for 2 hr and concentrated under reduced pressure. Theresidue was subjected to reversed-phase preparative HPLC, and a fractioneluted with water-acetonitrile (9:1-6:4) was collected, basified (pH 10)with saturated aqueous potassium carbonate solution, and extracted withethyl acetate. The extract was dried over anhydrous magnesium sulfate,and concentrated under reduced pressure. The residue was dissolved in0.7M hydrogen chloride-ethyl acetate (1.2 ml), and the mixture wasconcentrated under reduced pressure to give the object product (79 mg).

MS (ESI+, m/e) 530 (M+1)

In the same manner as in Example 50 or Example 53, the followingcompounds (Examples 56-59) were obtained.

Example 56N-{(3S,5R)-5-carbamoylpiperidin-3-yl}-4-methoxy-1-(4-methoxybutyl)-N-(2-methylpropyl)-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 460 (M+1)

Example 574-methoxy-1-(4-methoxybutyl)-N-(2-methylpropyl)-N-{(3S,5R)-5-(4H-1,2,4-triazol-3-yl)piperidin-3-yl}-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 484 (M+1)

Example 584-methoxy-1-(4-methoxybutyl)-N-(2-methylpropyl)-N-{(3S,5R)-5-(pyrrolidin-1-ylcarbonyl)piperidin-3-yl}-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 514 (M+1)

Example 594-methoxy-1-(4-methoxybutyl)-N-(2-methylpropyl)-N-{(3S,5R)-5-(piperidin-1-ylcarbonyl)piperidin-3-yl}-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 528 (M+1)

Reference Example 123 tert-butyl (5-methoxy-2-nitrophenyl)carbamate

5-Methoxy-2-nitrobenzoic acid (10.30 g) was suspended in toluene (200ml), triethylamine (9 ml) and diphenylphosphoryl azide (14 ml) wereadded dropwise at room temperature, and the mixture was stirred at 95°C. for 1.5 hr. Triethylamine (29 ml) and 2-methylpropan-2-ol (15 ml)were added, and the mixture was further stirred at 95° C. for 3 hr. Thereaction mixture was concentrated under reduced pressure, and dilutedwith ethyl acetate. 0.5M Hydrochloric acid (200 ml) was added, and themixture was filtered through celite. The organic layer of the filtratewas collected, washed with saturated aqueous sodium hydrogen carbonate,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was subjected to silica gel chromatography, and afraction eluted with ethyl acetate-hexane (5:95-1:1) was concentratedunder reduced pressure to give the object product (13.28 g).

¹H-NMR (CDCl₃) δ 1.55 (9H, s), 3.92 (3H, s), 6.58 (1H, dd), 8.16 (1H,s), 8.18 (1H, d), 10.10 (1H, br s)

In the same manner as in Reference Example 114, the following compound(Reference Example 124) was obtained.

Reference Example 124 tert-butyl(4-methoxybutyl)(5-methoxy-2-nitrophenyl)carbamate

¹H-NMR (CDCl₃) δ 1.25-1.54 (9H, m), 1.54-1.81 (4H, m), 3.30 (3H, s),3.34-3.44 (2H, m), 3.56-3.79 (2H, m), 3.89 (3H, s), 6.72-6.89 (2H, m),7.96-8.09 (1H, m)

In the same manner as in Reference Example 115, the following compound(Reference Example 125) was obtained.

Reference Example 125 5-methoxy-N-(4-methoxybutyl)-2-nitroaniline

¹H-NMR (CDCl₃) δ 1.68-1.88 (4H, m), 3.27-3.35 (2H, m), 3.35 (3H, s),3.45 (2H, t), 3.87 (3H, s), 6.15 (1H, d), 6.23 (1H, dd), 8.14 (1H, d),8.32 (1H, br s)

In the same manner as in Reference Example 116, the following compound(Reference Example 126) was obtained.

Reference Example 126 4-methoxy-2-(4-methoxybutylamino)aniline

¹H-NMR (CDCl₃) δ 1.65-1.81 (4H, m), 2.99 (2H, br s), 3.06-3.16 (2H, m),3.35 (3H, s), 3.38-3.47 (2H, m), 3.75 (3H, s), 3.70 (1H, br s), 6.17(1H, dd), 6.25 (1H, d), 6.64 (1H, d)

Reference Example 1276-methoxy-1-(4-methoxybutyl)-2-(trichloromethyl)-1H-benzimidazole

4-Methoxy-2-(4-methoxybutylamino)aniline (2.50 g) was dissolved inacetic acid (30 ml), methyl 2,2,2-trichloroethanimidate (1.62 ml) wasadded, and the mixture was stirred for 1.5 hr. The reaction mixture wasconcentrated under reduced pressure, and the residue was diluted withdiisopropyl ether, and washed with water. The organic layer was driedover anhydrous magnesium sulfate, and concentrated under reducedpressure to give the object product (1.75 g).

MS (ESI+, m/e) 351 (M+1)

Reference Example 128 tert-butyl(3S,5R)-3-{{{6-methoxy-1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

6-Methoxy-1-(4-methoxybutyl)-2-(trichloromethyl)-1H-benzimidazole (330mg) was dissolved in acetonitrile-water (2:1, 50 ml), and tert-butyl(3S,5R)-3-{(2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(350 mg) was added. Potassium carbonate (1.3 g) was added, and themixture was stirred at 80° C. for 5 hr. The reaction mixture wasconcentrated under reduced pressure, acidified (pH 3) with 6Mhydrochloric acid, and the mixture was extracted with ethyl acetate. Theextract was dried over anhydrous magnesium sulfate, and concentratedunder reduced pressure. The residue was subjected to silica gelchromatography, and a fraction eluted with ethyl acetate-hexane(3:7)-ethyl acetate was concentrated under reduced pressure. The residuewas further subjected to reversed-phase preparative HPLC, and a fractioneluted with water-acetonitrile (9:1-6:4) was collected, basified (pH 10)with saturated aqueous potassium carbonate solution, and extracted withethyl acetate. The extract was dried over anhydrous magnesium sulfate,and concentrated under reduced pressure to give the object product (82mg).

MS (ESI+, m/e) 630 (M+1)

Reference Example 129(3R,5S)-1-(tert-butoxycarbonyl)-5-{{{6-methoxy-1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}piperidine-3-carboxylicacid

6-Methoxy-1-(4-methoxybutyl)-2-(trichloromethyl)-1H-benzimidazole (1.42g) was dissolved in acetonitrile-water (2:1, 150 ml), 1-tert-butyl3-methyl(3R,5S)-5-{(2-methylpropyl)amino}piperidine-1,3-dicarboxylate(1.02 g) was added, potassium carbonate (5.5 g) was added and themixture was stirred at 80° C. for 19 hr. The reaction mixture wasconcentrated under reduced pressure, acidified (pH3) with 6Mhydrochloric acid, and extracted with ethyl acetate. The extract wasdried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was subjected to silica gel chromatography, and afraction eluted with ethyl acetate-hexane (5:95)-ethyl acetate-ethylacetate-methanol (85:15) was concentrated under reduced pressure. Theresidue was subjected to reversed-phase preparative HPLC, and a fractioneluted with water-acetonitrile (9:1-6:4) was collected, basified (pH 10)with saturated aqueous potassium carbonate solution, and extracted withethyl acetate. The extract was dried over anhydrous magnesium sulfate,and concentrated under reduced pressure to give the object product (460mg).

MS (ESI+, m/e) 561 (M+1)

In the same manner as in Reference Example 105, the following compound(Reference Example 130) was obtained.

Reference Example 130 tert-butyl(3R,5S)-3-carbamoyl-5-{{{6-methoxy-1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}piperidine-1-carboxylate

MS (ESI+, m/e) 560 (M+1)

In the same manner as in Reference Example 107, the following compound(Reference Example 131) was obtained.

Reference Example 131 tert-butyl(3S,5R)-3-{{{6-methoxy-1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}-5-(pyrrolidin-1-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 614 (M+1)

Example 606-methoxy-1-(4-methoxybutyl)-N-(2-methylpropyl)-N-{(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl}-1H-benzimidazole-2-carboxamidedihydrochloride

tert-Butyl(3S,5R)-3-{{{6-methoxy-1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(82 mg) was dissolved in 2M hydrogen chloride-ethyl acetate (3 ml), andthe mixture was stirred at room temperature for 1 hr and concentrated togive the object product (78 mg).

MS (ESI+, m/e) 530 (M+1)

In the same manner as in Example 60, the following compounds (Examples61-62) were obtained.

Example 61N-{(3S,5R)-5-carbamoylpiperidin-3-yl}-6-methoxy-1-(4-methoxybutyl)-N-(2-methylpropyl)-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 460 (M+1)

Example 626-methoxy-1-(4-methoxybutyl)-N-(2-methylpropyl)-N-{(3S,5R)-5-(pyrrolidin-1-ylcarbonyl)piperidin-3-yl}-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 514 (M+1)

Reference Example 132 tert-butyl(3S,5R)-3-{(1H-benzimidazol-2-ylcarbonyl)(2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

2-(Trichloromethyl)-1H-benzimidazole (2.00 g) and tert-butyl(3S,5R)-3-{(2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(2.84 g) were dissolved in tetrahydrofuran-water (3:2,150 ml), sodiumhydrogen carbonate (6.45 g) was added and the mixture was stirred atroom temperature for 1 hr. The reaction mixture was concentrated underreduced pressure, diluted with water, and the mixture was extracted withethyl acetate. The extract was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The precipitated white solid was collected by filtration, washed withethyl acetate-hexane (1:1) and dried to give the object product (3.03g).

¹H-NMR (CDCl₃) δ 0.86-1.01 (6H, m), 1.30-1.50 (9H, m), 1.89-2.64 (3H,m), 2.68-3.08 (2H, m), 3.22-4.01 (10H, m), 4.07-4.44 (3H, m), 5.53-6.12(1H, m), 7.27-7.42 (2H, m), 7.52 (1H, t), 7.61-7.86 (1H, m), 10.15-10.52(1H, m)

MS (ESI+, m/e) 514 (M+1)

Reference Example 133 tert-butyl(3S,5R)-3-{(2-methylpropyl){{1-(2-phenylethyl)-1H-benzimidazol-2-yl}carbonyl}amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

tert-Butyl(3S,5R)-3-{(1H-benzimidazol-2-ylcarbonyl)(2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(147 mg) was dissolved in dimethylformamide (12 ml),(2-bromoethyl)benzene (58 μl) and cesium carbonate (200 mg) were addedand the mixture was stirred at 65° C. for 3 hr. (2-Bromoethyl)benzene(58 μl) was added, and the mixture was further stirred for 2 hr. Thereaction mixture was concentrated under reduced pressure, diluted withwater, and extracted with ethyl acetate. The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was subjected to silicagel chromatography, and a fraction eluted with ethyl acetate-hexane(1:9)-ethyl acetate was concentrated under reduced pressure to give theobject product (164 mg).

MS (ESI+, m/e) 618 (M+1)

Reference Example 134 2-(thiophen-2-yl)ethyl methanesulfonate

2-(Thiophen-2-yl)ethanol (1.05 g) was dissolved in tetrahydrofuran (25ml), triethylamine (1.63 ml) and methanesulfonyl chloride (725 μl) wereadded and the mixture was stirred for 20 min. Saturated aqueous sodiumhydrogen carbonate (50 ml) was added to the reaction mixture, and themixture was extracted with diisopropyl ether. The extract was washedwith saturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure to give the object product (1.62 g).

¹H-NMR (CDCl₃) δ 2.93 (3H, s), 3.28 (2H, ddd), 4.42 (2H, t), 6.90-6.93(1H, m), 6.96 (1H, dd), 7.20 (1H, dd)

Reference Example 135

tert-butyl (3S,5R)-3-{(2-methylpropyl){{1-(2-(thiophen-2-yl)ethyl)-1H-benzimidazol-2-yl}carbonyl}amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

tert-Butyl(3S,5R)-3-{(1H-benzimidazol-2-ylcarbonyl)(2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(150 mg) was dissolved in dimethylformamide (10 ml),2-(thiophen-2-yl)ethyl methanesulfonate (90 mg) and cesium carbonate(190 mg) were added and the mixture was stirred at 65° C. for 30 min.2-Thiophen-2-ylethyl methanesulfonate (90 mg) was added, and the mixturewas further stirred for 1 hr. The reaction mixture was concentratedunder reduced pressure, diluted with water, and extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was subjected to silica gel chromatography, and a fractioneluted with ethyl acetate-hexane (1:9)-ethyl acetate was concentratedunder reduced pressure to give the object product (156 mg).

MS (ESI+, m/e) 624 (M+1)

In the same manner as in Example 60, the following compounds (Examples63-64) were obtained.

Example 63N-(2-methylpropyl)-N-{(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl}-1-(2-phenylethyl)-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 518 (M+1)

Example 64N-(2-methylpropyl)-N-{(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl}-1-(2-(thiophen-2-yl)ethyl)-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 524 (M+1)

In the same manner as in the method shown in Reference Example 106, thecompound described in the following Reference Example 136 was obtained.

Reference Example 136 tert-butyl(3S,5R)-3-{{{1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}-5-(4H-1,2,4-triazol-3-yl)piperidine-1-carboxylate

MS (ESI+, m/e) 454 (M+1)

Reference Example 137 tert-butyl(3R,5S)-3-cyano-5-{{{1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}piperidine-1-carboxylate

tert-Butyl(3R,5S)-3-carbamoyl-5-{{{1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}piperidine-1-carboxylate(1.01 g) was dissolved in pyridine (10 ml), trifluoroacetic anhydride(570 μl) was added at 0° C., and the mixture was stirred at roomtemperature for 2 hr. The reaction mixture was concentrated underreduced pressure, and diluted with ethyl acetate. 1M Hydrochloric acidwas added, and the mixture was extracted with ethyl acetate. The extractwas washed with saturated brine, dried over anhydrous magnesium sulfate,and concentrated under reduced pressure. The residue was subjected tosilica gel chromatography, and a fraction eluted with ethylacetate-hexane (5:95)-ethyl acetate was concentrated under reducedpressure to give the object product (1.01 g).

MS (ESI+, m/e) 512 (M+1)

Reference Example 138 tert-butyl(3S,5R)-3-{{{1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}-5-(1,2,4-oxadiazol-3-yl)piperidine-1-carboxylate

Hydroxylamine hydrochloride (383 mg) was dissolved in dimethyl sulfoxide(10 ml), and the mixture was stirred at 40° C. for 30 min. Sodiumhydrogen carbonate (463 mg) was added, and the mixture was stirred at50° C. for 1 hr. A solution of tert-butyl(3R,5S)-3-cyano-5-{{{1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}piperidine-1-carboxylate(282 mg) in dimethyl sulfoxide (10 ml) was further added, and themixture was stirred at 90° C. for 3 hr. The reaction mixture was allowedto cool to room temperature, diluted with water, and extracted withethyl acetate. The extract was dried over anhydrous magnesium sulfate,and concentrated under reduced pressure. The residue was dissolved intrimethyl orthoformate (5 ml) and the mixture was stirred at 100° C. for4 hr. The reaction mixture was concentrated under reduced pressure, andthe residue was subjected to silica gel chromatography, and a fractioneluted with ethyl acetate-hexane (5:95-3:7) was concentrated underreduced pressure to give the object product (230 mg).

MS (ESI+, m/e) 555 (M+1)

Reference Example 139 tert-butyl(3S,5R)-3-{{{1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)piperidine-1-carboxylate

Hydroxylamine hydrochloride (418 mg) was dissolved in dimethyl sulfoxide(10 ml), and the mixture was stirred at 40° C. for 30 min. Sodiumhydrogen carbonate (506 mg) was added, and the mixture was stirred at50° C. for 1 hr. A solution of tert-butyl(3R,55S)-3-cyano-5-{{{1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}piperidine-1-carboxylate(308 mg) in dimethyl sulfoxide (10 ml) was further added, and themixture was stirred at 90° C. for 3 hr. The reaction mixture was allowedto cool to room temperature, diluted with water, and the mixture wasextracted with ethyl acetate. The extract was dried over anhydrousmagnesium sulfate, concentrated under reduced pressure, and the residuewas dissolved in tetrahydrofuran (15 ml). 1,1′-Carbonylbis(1H-imidazole)(490 mg) and 1,8-diazabicyclo{5.4.0}undec-7-ene (450 μl) were added andthe mixture was stirred at room temperature for 1 hr. The reactionmixture was concentrated under reduced pressure, and the residue wasdiluted with ethyl acetate. The mixture was washed with 0.5Mhydrochloric acid and saturated brine, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue wassubjected to silica gel chromatography, and a fraction eluted with ethylacetate-hexane (5:95)-ethyl acetate was concentrated under reducedpressure to give the object product (256 mg).

MS (ESI+, m/e) 571 (M+1)

Reference Example 140 tert-butyl(3S,5R)-3-{{{1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}-5-(1H-tetrazol-5-yl)piperidine-1-carboxylate

tert-Butyl(3R,5S)-3-cyano-5-{{{1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}piperidine-1-carboxylate(320 mg) was dissolved in tetrahydrofuran (20 ml),azido(trimethyl)silane (1.5 ml) and dibutyl(oxo)stannane (100 mg) wereadded, and the mixture was heated under reflux with stirring for 43 hr.The reaction mixture was concentrated under reduced pressure, and theresidue was subjected to silica gel chromatography, and a fractioneluted with ethyl acetate-ethyl acetate-methanol (8:2) was concentratedunder reduced pressure to give the object product (304 mg).

MS (ESI+, m/e) 555 (M+1)

In the same manner as in Example 60, the following compounds (Examples65-68) were obtained.

Example 651-(4-methoxybutyl)-N-(2-methylpropyl)-N-{(3S,5R)-5-(4H-1,2,4-triazol-3-yl)piperidin-3-yl}-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 454 (M+1)

Example 66N-{(3S,5R)-5-cyanopiperidin-3-yl}-1-(4-methoxybutyl)-N-(2-methylpropyl)-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 412 (M+1)

Example 671-(4-methoxybutyl)-N-(2-methylpropyl)-N-{(3S,5R)-5-(1,2,4-oxadiazol-3-yl)piperidin-3-yl}-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 455 (M+1)

Example 681-(4-methoxybutyl)-N-(2-methylpropyl)-N-{(3S,5R)-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)piperidin-3-yl}-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 471 (M+1)

Example 691-(4-methoxybutyl)-N-(2-methylpropyl)-N-{(3S,5R)-5-(H-tetrazol-5-yl)piperidin-3-yl}-1H-benzimidazole-2-carboxamidedihydrochloride

tert-Butyl(3S,5R)-3-{{{1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}-5-(1H-tetrazol-5-yl)piperidine-1-carboxylate(304 mg) was dissolved in 2M hydrogen chloride-ethyl acetate (2 ml), andthe mixture was stirred at room temperature for 1 hr. The reactionmixture was concentrated, and ethyl acetate-diisopropyl ether was added.The precipitate was collected by filtration, and washed with ethylacetate-diisopropyl ether to give the object product (219 mg).

MS (ESI+, m/e) 455 (M+1)

In the same manner as in Reference Example 106, the following compound(Reference Example 141) was obtained.

Reference Example 141 tert-butyl(3S,5R)-3-[{[5-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(4H-1,2,4-triazol-3-yl)piperidine-1-carboxylate

MS (ESI+, m/e) 572 (M+1)

Reference Example 142 tert-butyl(3S,5R)-3-{[(benzyloxy)carbonyl](2-methylpropyl)amino}-5-(hydroxymethyl)piperidine-1-carboxylate

Powder calcium chloride (0.49 g) was suspended in ethanol (10 ml),sodium borohydride (0.34 g) was added while cooling to 0° C., and themixture was stirred at 0° C. for 30 min. A solution (10 ml) of1-tert-butyl3-methyl(3R,5S)-5-{[(benzyloxy)carbonyl](2-methylpropyl)amino}piperidine-1,3-dicarboxylate(1.00 g) in THF was added to the reaction suspension, and the mixturewas stirred at 0° C. for 8 hr. 5% Aqueous sodium hydrogen sulfatesolution was added to the reaction mixture for neutralization and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure to give the object product (0.88g) as an oil.

¹H-NMR (CDCl₃) δ 0.90 (6H, d), 1.22-1.38 (3H, m), 1.46 (9H, s), 1.69(1H, dt), 2.23-2.39 (2H, m), 2.44-2.59 (1H, m), 2.47 (2H, d), 2.74 (1H,br s), 3.69 (3H, s), 4.18-4.34 (2H, m)

Reference Example 143 tert-butyl(3S,5S)-3-[(2-methylpropyl)amino]-5-[(2-oxopyrrolidin-1-yl)methyl]piperidine-1-carboxylate

To a solution of tert-butyl(3S,5R)-3-{[(benzyloxy)carbonyl](2-methylpropyl)amino}-5-(hydroxymethyl)piperidine-1-carboxylate(0.47 g) in THF (15 ml) were added phthalimide (0.40 g), diisopropylazodicarboxylate (1.59 g) and triphenylphosphine (0.66 g) at roomtemperature, and the mixture was stirred at room temperature for 15 hr.The reaction mixture was concentrated under reduced pressure, theresidue was diluted with water, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theobtained residue was subjected to silica gel chromatography, and afraction eluted with ethyl acetate-hexane (1:9-1:2) was concentratedunder reduced pressure. The obtained residue was dissolved in ethanol(10 ml), hydrazine hydrate (95 μl) was added, and the mixture was heatedunder reflux for 3 hr. The mixture was allowed to cool to roomtemperature, the precipitate was filtered off, and the filtrate wasconcentrated under reduced pressure. The residue was dissolved in THF (5ml), diisopropylethylamine (0.29 μl) and 4-bromobutyryl chloride (0.16ml) were added at 0° C., and the mixture was stirred at 0° C. for 1 hr.The reaction mixture was diluted with water, and extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was dissolved in THF (10 ml), potassium tert-butoxide (0.38 g)was added at 0° C., and the mixture was stirred at 0° C. for 1 hr. Thereaction mixture was concentrated under reduced pressure, and theresidue was diluted with water, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theobtained residue was subjected to silica gel chromatography, and afraction eluted with ethyl acetate-hexane (1:3-1:0) was concentratedunder reduced pressure. The residue was dissolved in ethanol (10 ml),and 10% palladium-carbon (50% in water: 50 mg) was added. The reactionmixture was stirred under a hydrogen (normal pressure) at roomtemperature for 15 hr. The palladium catalyst was filtered off, and thefiltrate was concentrated under reduced pressure to give the objectproduct (0.30 g).

¹H-NMR (CDCl₃) δ 0.90 (6H, d), 1.45 (11H, s), 1.68 (1H, dt), 2.04 (2H,qd), 1.77-2.10 (2H, m), 2.21-2.54 (6H, m), 3.18 (2H, br s), 3.40 (2H,ddd), 4.02 (1H, br s), 4.26 (1H, br s)

In the same manner as in Reference Example 64, the following compound(Reference Example 144) was obtained.

Reference Example 144 tert-butyl(3S,5S)-3-[(1H-benzimidazol-2-ylcarbonyl)(2-methylpropyl)amino]-5-[(2-oxopyrrolidin-1-yl)methyl]piperidine-1-carboxylate

MS (ESI+, m/e) 498 (M+1)

In the same manner as in Reference Example 69, the following compound(Reference Example 145) was obtained.

Reference Example 145 tert-butyl(3S,5S)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-[(2-oxopyrrolidin-1-yl)methyl]piperidine-1-carboxylate

MS (ESI+, m/e) 584 (M+1)

In the same manner as in Example 60, the following compound (Example 70)was obtained.

Example 701-(4-methoxybutyl)-N-(2-methylpropyl)-N-{(3S,5R)-5-[(2-oxopyrrolidin-1-yl)methyl]piperidin-3-yl}-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 484 (M+1)

Reference Example 146 tert-butyl(3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

A solution of tert-butyl(3S,5R)-3-[(1H-benzimidazol-2-ylcarbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(200 mg), 4-methoxybutyl methanesulfonate (107 mg) and cesium carbonate(254 mg) in N,N-dimethylacetamide (5 ml) was stirred at 60° C. for 15hr. After cooling to room temperature, the reaction mixture was dilutedwith water and extracted with ethyl acetate (10 ml×2). The extract waswashed with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wassubjected to silica gel column chromatography, and a fraction elutedwith ethyl acetate-hexane (5:95-3:7) was concentrated under reducedpressure to give the object product (190 mg).

Reference Example 1471-(tert-butoxycarbonyl)-5-(methoxycarbonyl)piperidine-3-carboxylic acid

1-tert-Butyl 3,5-dimethyl piperidine-1,3,5-tricarboxylate (75 g) wasdissolved in methanol (375 ml), and 2M aqueous sodium hydroxide solution(125 ml) was added dropwise at room temperature. The reaction mixturewas stirred at room temperature for 14 hr, and methanol was evaporatedunder reduced pressure. The concentrate was diluted with saturatedaqueous sodium hydrogen carbonate solution (100 ml) and washed twicewith ethyl acetate. The basic aqueous layer was acidified (pH 2) with 6Mhydrochloric acid, and the mixture was extracted with ethyl acetate. Theextract was dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure to give the object product (71 g).

¹H-NMR (CDCl₃) δ 1.33-1.50 (9H, m), 1.60-1.82 (1H, m), 1.96-2.22 (1H,m), 2.41-2.58 (2H, m), 2.62-2.91 (2H, m), 3.34-3.91 (1H, m), 3.71 (3H,s), 4.37 (1H, br s), 7.55-8.47 (1H, m)

Example 711-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamide

tert-Butyl(3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(5.85 g) was dissolved in methanol (20 ml), 4M hydrogen chloride-ethylacetate (20 ml) was added, and the mixture was stirred at roomtemperature for 15 hr. The reaction mixture was concentrated, theresidue was diluted with aqueous sodium bicarbonate, and, the mixturewas extracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. The residue was subjected to basicsilica gel column chromatography, and a fraction eluted with ethylacetate-methanol (9:1) was concentrated under reduced pressure to givethe object product (4.40 g).

MS (ESI+, m/e) 500 (M+1)

Example 721-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidemethanesulfonate

Crude crystals (163 g) of1-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidemethanesulfonate were dissolved in 2-butanone (1600 ml) with heating(65° C.), and heptane (1600 ml) was added dropwise while keeping at 60°C. or above. The seed crystal was added, and the mixture was stirred at50-55° C. for 1 hr and at room temperature for 12 hr and filtered. Thecrystals were washed with a small amount of 2-butanone-heptane (mixingratio 1:2), and dried under reduced pressure to give the object product(155.6 g).

¹H-NMR (DMSO-d₆.) δ 0.68-0.74 (2H, m), 0.89-0.99 (4H, m), 1.42-1.60 (2H,m), 1.70-1.87 (2H, m), 1.95-2.17 (2H, m), 2.15-2.39 (4H, m), 2.80-3.85(20H, m), 4.15-4.40 (3H, m), 7.25-7.43 (2H, m), 7.62-7.75 (2H, m), 8.30(1H, br s), 9.09 (1H, br s)

MS (ESI+, m/e) 500 (M+1)

melting point: 137-138° C.

Reference Example 149 tert-butyl(3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate

(3R,5S)-1-(tert-Butoxycarbonyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid (7.5 g), WSC.HCL (4.06 g) and HOBt (3.25 g) were dissolved in DMF(50 ml), N-methoxymethylamine hydrochloride (1.38 g) and triethylamine(7.88 ml) were added and the mixture was stirred at room temperature for15 hr. The reaction mixture was diluted with water, and the mixture wasextracted with ethyl acetate. The extract was washed with water andbrine, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. The residue was subjected to silicagel column chromatography, and a fraction eluted with ethylacetate-hexane (1:4-9:1) was concentrated under reduced pressure to givethe object product (4.76 g).

¹H-NMR (CDCl₃) δ 0.73 (3H, d), 1.01 (3H, dd), 1.30 (4H, s), 1.48 (5H,s), 1.67 (2H, dt), 1.91-2.03 (2H, m), 2.20 (1H, t), 2.41 (1H, q),2.60-3.13 (5H, m), 3.15-3.24 (3H, m), 3.32 (3H, d), 3.34-3.47 (3H, m),3.67-3.81 (3H, m), 3.92-4.47 (5H, m), 7.27-7.40 (2H, m), 7.41-7.53 (1H,m), 7.72 (1H, dd), 7.84 (1H, d)

MS (ESI+, m/e) 574 (M+1)

Reference Example 150 tert-butyl(3S,5R)-5-acetyl-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate

To a solution of tert-butyl(3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate(1.06 g) in THF (20 ml) was added 1M-methyl magnesium bromide-THFsolution (9.24 ml), and the mixture was stirred at room temperature for5 hr. The reaction mixture was poured into saturated aqueous ammoniumchloride solution, and the mixture was extracted with ethyl acetate. Theextract was washed with water and saturated brine, and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure. The residue was subjected to silica gel column chromatography,and a fraction eluted with ethyl acetate-hexane (1:9-3:2) wasconcentrated under reduced pressure to give the object product (0.59 g).

¹H-NMR (CDCl₃) δ 0.76 (3H, d), 1.01 (3H, d), 1.31 (4H, s), 1.49 (5H, s),1.79 (2H, br s), 2.00 (2H, br s), 2.21 (3H, s), 2.27-2.47 (2H, m), 2.56(1H, br s), 2.74 (2H, d), 3.22-3.37 (3H, m), 3.42 (3H, t), 3.78 (2H, brs), 4.31 (5H, d), 7.28-7.41 (2H, m), 7.45 (1H, d), 7.79 (1H, d)

MS (ESI+, m/e) 529 (M+1)

Reference Example 151 tert-butyl(3R,5S)-3-(1-hydroxyethyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate

To a solution of tert-butyl(3R,5S)-3-acetyl-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate(0.40 g) in ethanol (10 ml) was added sodium borohydride (29 mg), andthe mixture was stirred at room temperature for 1 hr. The reactionmixture was concentrated under reduced pressure, and the residue wasdiluted with water. The mixture was acidified with 5% aqueous potassiumhydrogen sulfate solution, and extracted with ethyl acetate. The extractwas washed with water and saturated brine, and dried over anhydroussodium sulfate. The solvent was evaporated under reduced pressure. Theresidue was subjected to silica gel column chromatography, and afraction eluted with ethyl acetate-hexane (1:9-3:1) was concentratedunder reduced pressure to give the object product (0.40 g).

¹H-NMR (CDCl₃) δ 0.77 (4H, dd), 1.02 (2H, d), 1.16-1.27 (3H, m), 1.33(4H, d), 1.48 (7H, s), 1.83 (1H, br s), 1.98 (2H, d), 2.11-2.90 (3H, m),3.30 (1H, d), 3.33 (3H, s), 3.35-3.46 (3H, m), 3.66 (4H, br s),4.17-4.48 (4H, m), 7.28-7.40 (2H, m), 7.40-7.48 (1H, m), 7.79 (1H, d)

MS (ESI+, m/e) 531 (M+1)

Reference Example 152 tert-butyl(3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-propanoyl-piperidine-1-carboxylate

To a solution of tert-butyl(3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate(22.7 g) in THF (20 ml) was added 1M-ethylmagnesium bromide-THF solution(119 ml) at room temperature, and the mixture was stirred at roomtemperature for 5 hr. The reaction mixture was poured into saturatedaqueous ammonium chloride solution, and the mixture was extracted withethyl acetate. The extract was washed with water and saturated brine,and dried over anhydrous sodium sulfate. The solvent was evaporatedunder reduced pressure. The residue was subjected to silica gel columnchromatography, and a fraction eluted with ethyl acetate-hexane(1:9-3:2) was concentrated under reduced pressure to give the objectproduct (14.96 g).

MS (ESI+, m/e) 543 (M+1)

Reference Example 153 tert-butyl(3R,5S)-3-(1-hydroxypropyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate

To a solution of tert-butyl(3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-propanoyl-piperidine-1-carboxylate(2.60 g) in ethanol (30 ml) was added sodium borohydride (181 mg), andthe mixture was stirred at room temperature for 1 hr. The reactionmixture was concentrated under reduced pressure, and the residue wasdiluted with water, acidified with 5% aqueous potassium hydrogen sulfatesolution, and extracted with ethyl acetate. The extract was washed withwater and saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was subjectedto silica gel column chromatography, and a fraction eluted with ethylacetate-hexane (1:9-1:1) was concentrated under reduced pressure to givethe object product (2.02 g).

¹H-NMR (CDCl₃) δ 0.76 (4H, d), 0.91-1.08 (5H, m), 1.33 (3H, d), 1.48(6H, s), 1.55 (2H, d), 1.64-1.90 (5H, m), 1.91-2.03 (2H, m), 2.10-2.42(2H, m), 2.59 (1H, d), 3.31 (1H, d), 3.33 (2H, s), 3.42 (4H, t), 3.65(2H, br s), 4.17-4.46 (4H, m), 7.27-7.39 (2H, m), 7.39-7.51 (1H, m),7.69-7.85 (1H, m)

MS (ESI+, m/e) 545 (M+1)

Example 73N-{(3S,5R)-5-[(1R)-1-hydroxy-2-methoxyethyl]piperidin-3-yl}-1-(4-methoxybutyl)-N-(2-methylpropyl)-1H-benzimidazole-2-carboxamidedihydrochloride (Example 73-1) andN-{(3S,5R)-5-[(1S)-1-hydroxy-2-methoxyethyl]piperidin-3-yl}-1-(4-methoxybutyl)-N-(2-methylpropyl)-1H-benzimidazole-2-carboxamidedihydrochloride (Example 73-2)

tert-Butyl(3R,5S)-3-(1-hydroxy-2-methoxyethyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate(1.34 g) was optically resolved by normal phase chiral HPLC under thefollowing conditions to give a first elution component (598 mg) and asecond elution component (549 mg).

column: CHIRALPAK IC 50 mm ID×500 mL

mobile phase: hexane-ethanol (700:300)

flow rate: 60 ml/min

temperature: 30° C.

detection: UV (220 nm)

injection volume·concentration: 300 mg/load (5 mg/ml)

The obtained first elution component (495 mg) was dissolved in ethanol(1 ml), 12M hydrochloric acid (0.70 ml) was added and the mixture wasstirred at room temperature for 1 hr. The reaction mixture wasconcentrated under reduced pressure, and the residue was dissolved inethanol, and ethanol was evaporated under reduced pressure. Thisoperation was repeated twice to give the object product (425 mg) ofExample compound 73-1.

Example 73-1 Spectrum Data

¹H-NMR (CDCl₃) δ 0.71 (2H, dd), 0.95 (4H, dd), 1.38-1.63 (2H, m),1.66-1.86 (3H, m), 1.86-2.04 (1H, m), 2.12 (2H, dd), 2.59-2.91 (1H, m),3.02 (1H, d), 3.09-3.22 (4H, m), 3.24-3.39 (9H, m), 3.50 (2H, br s),3.62 (1H, br s), 4.15 (2H, br s), 4.21-4.39 (2H, m), 7.15-7.53 (2H, m),7.55-7.87 (2H, m), 8.33-9.18 (1H, m), 9.43 (1H, br s)

MS (ESI+, m/e) 461 (M+1)

The obtained second elution component (447 mg) was dissolved in ethanol(1 ml), 12M hydrochloric acid (0.70 ml) was added at room temperatureand the mixture was stirred for 1 hr. The reaction mixture wasconcentrated under reduced pressure, the residue was dissolved inethanol, and ethanol was evaporated under reduced pressure. Thisoperation was repeated twice to give the object product (365 mg) ofExample compound 73-2.

Example 73-2 Spectrum Data

¹H-NMR (CDCl₃) δ 0.71 (2H, dd), 0.81-1.12 (4H, m), 1.31-1.61 (2H, m),1.62-1.98 (5H, m), 1.98-2.23 (2H, m), 2.57-2.87 (1H, m), 3.14 (1H, d),3.18-3.23 (3H, m), 3.23-3.39 (10H, m), 3.39-3.63 (3H, m), 4.23-4.38 (3H,m), 7.16-7.51 (2H, m), 7.55-7.86 (2H, m), 8.29-9.11 (1H, m), 9.38 (1H,br s)

MS (ESI+, m/e) 461 (M+1)

Example 74N-{(3S,5R)-5-[(1S)-1-hydroxyethyl]piperidin-3-yl}-1-(4-methoxybutyl)-N-(2-methylpropyl)-1H-benzimidazole-2-carboxamidedihydrochloride (Example 74-1) andN-{(3S,5R)-5-[(1R)-1-hydroxyethyl]piperidin-3-yl}-1-(4-methoxybutyl)-N-(2-methylpropyl)-1H-benzimidazole-2-carboxamidedihydrochloride (Example 74-2)

tert-Butyl(3R,5S)-3-(1-hydroxyethyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate(3.2 g) was optically resolved by normal phase chiral HPLC under thefollowing conditions to give a first elution component (1.31 g) and asecond elution component (1.22 g).

column: CHIRALPAK IC 50 mm ID×500 mL

mobile phase: hexane-ethanol (900:100)

flow rate: 80 ml/min

temperature: 30° C.

detection: UV (220 nm)

injection volume·concentration: 300 mg/load (5 mg/ml)

The obtained first elution component (1.1 g) was dissolved in 10%hydrogen chloride containing methanol solution (40 ml), and the mixturewas stirred at room temperature for 15 hr. The reaction mixture wasconcentrated under reduced pressure, the residue was dissolved inethanol, and ethanol was evaporated under reduced pressure. Thisoperation was repeated twice to give the object product (0.90 g) ofExample compound 74-1.

Example 74-1 Spectrum Data

¹H-NMR (CDCl₃) δ 0.72 (3H, dd), 0.84-1.18 (7H, m), 1.45-1.66 (3H, m),1.67-1.98 (3H, m), 2.00-2.19 (2H, m), 2.54-2.81 (1H, m), 2.92-3.23 (5H,m), 3.25-3.40 (4H, m), 3.40-3.70 (3H, m), 4.07-4.47 (3H, m), 7.23-7.51(2H, m), 7.54-7.91 (2H, m), 8.56-9.55 (1H, m), 9.86 (1H, d)

MS (ESI+, m/e) 431 (M+1)

The obtained second elution component (1.0 g) was dissolved in 10%hydrogen chloride containing methanol solution (40 ml) was stirred atroom temperature for 15 hr. The reaction mixture was concentrated underreduced pressure, the residue was dissolved in ethanol, and ethanol wasevaporated under reduced pressure. This operation was repeated twice togive the object product (0.86 g) of Example compound 74-2.

Example 74-2 Spectrum Data

¹H-NMR (CDCl₃) δ 0.71 (3H, dd), 0.94 (3H, d), 1.09 (3H, dd), 1.27-1.64(3H, m), 1.70 (1H, s), 1.74-2.00 (4H, m), 2.00-2.29 (1H, m), 2.54-2.76(1H, m), 3.11 (1H, d), 3.20 (4H, d), 3.24-3.62 (7H, m), 4.32 (3H, d),7.16-7.54 (2H, m), 7.72 (2H, q), 8.27-9.22 (1H, m), 9.36-9.56 (1H, m)

MS (ESI+, m/e) 431 (M+1)

Example 75N-{(3S,5R)-5-[(1S)-1-hydroxypropyl]piperidin-3-yl}-1-(4-methoxybutyl)-N-(2-methylpropyl)-1H-benzimidazole-2-carboxamidedihydrochloride (Example 75-1) andN-{(3S,5R)-5-[(1R)-1-hydroxypropyl]piperidin-3yl}-1-(4-methoxybutyl)-N-(2-methylpropyl)-1H-benzimidazole-2-carboxamidedihydrochloride (Example 75-2)

tert-Butyl(3R,5S)-3-(1-hydroxypropyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate(2.11 g) was optically resolved by normal phase chiral HPLC under thefollowing conditions to give a first elution component (1.26 g) and asecond elution component (1.70 g).

column: CHIRALPAK IC 50 mm ID×500 mL

mobile phase: hexane-ethanol (900:100)

flow rate: 80 ml/min

temperature: 30° C.

detection: UV (220 nm)

injection volume·concentration: 300 mg/load (5 mg/ml)

The obtained first elution component (1.03 g) was dissolved in ethanol(2 ml), 12M hydrochloric acid (1.5 ml) was added and the mixture wasstirred at room temperature for 1 hr. The reaction mixture wasconcentrated under reduced pressure, the residue was dissolved inethanol, and ethanol was evaporated under reduced pressure. Thisoperation was repeated twice to give the object product (0.95 g) ofExample compound 75-1.

Example 75-1 Spectrum Data

¹H-NMR (CDCl₃) δ 0.71 (2H, dd), 0.79-1.11 (7H, m), 1.32-1.58 (4H, m),1.60-1.68 (1H, m), 1.70-1.85 (3H, m), 1.87-2.20 (2H, m), 2.59-2.87 (1H,m), 3.00 (1H, d), 3.08-3.23 (4H, m), 3.23-3.41 (6H, m), 3.49 (1H, d),3.89-4.23 (2H, m), 4.23-4.55 (2H, m), 7.16-7.52 (2H, m), 7.55-7.86 (2H,m), 8.24-9.18 (1H, m), 9.21-9.57 (1H, m)

MS (ESI+, m/e) 445 (M+1)

The obtained second elution component (0.85 g) was dissolved in ethanol(2 ml), 12M hydrochloric acid (1.5 ml) was added and the mixture wasstirred at room temperature for 1 hr. The reaction mixture wasconcentrated under reduced pressure, the residue was dissolved inethanol, and ethanol was evaporated under reduced pressure. Thisoperation was repeated twice to give the object product (0.78 g) ofExample compound 75-2.

Example 75-2 Spectrum Data

¹H-NMR (CDCl₃) δ 0.71 (2H, dd), 0.78-1.01 (7H, m), 1.26-1.66 (4H, m),1.66-1.86 (4H, m), 1.93 (1H, d), 2.02-2.23 (1H, m), 2.53-2.84 (1H, m),3.03-3.24 (5H, m), 3.31 (5H, q), 3.37-3.56 (2H, m), 4.16 (2H, br s),4.22-4.44 (2H, m), 7.16-7.54 (2H, m), 7.54-7.87 (2H, m), 8.16-9.27 (1H,m), 9.36-9.84 (1H, m)

MS (ESI+, m/e) 445 (M+1)

Example 76N-[(3S,5R)-5-(1-hydroxypropyl)piperidin-3-yl]-1-(4-methoxybutyl)-N-(2-methylpropyl)-1H-benzimidazole-2-carboxamidedihydrochloride

To a solution of tert-butyl(3R,5S)-3-(1-hydroxypropyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate(200 mg) in ethanol (1 ml) was added 12M hydrochloric acid (0.30 ml),and the mixture was stirred at room temperature for 1 hr. The reactionmixture was concentrated under reduced pressure, the residue wasdissolved in ethanol, and ethanol was evaporated under reduced pressure.This operation was repeated twice to give the object product (140 mg).

MS (ESI+, m/e) 445 (M+1)

Reference Example 154 tert-butyl(3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(1H-pyrazol-1-ylmethyl)piperidine-1-carboxylate

To a solution of tert-butyl(3R,5S)-3-(hydroxymethyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate(517 mg) and triethylamine (0.21 ml) in ethyl acetate (20 ml) was addeddropwise methanesulfonyl chloride (0.09 ml) at 0° C., and the mixturewas stirred at 0° C. for 1 hr. The reaction mixture was washed withwater and saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was dissolvedin DMF (5 ml), pyrazole (136 mg) and cesium carbonate (489 mg) wereadded and the mixture was stirred at 90° C. for 7 hr. The reactionmixture was cooled to room temperature, diluted with water and extractedwith ethyl acetate. The extract was washed with water and brine, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure. The residue was subjected to silica gel columnchromatography, and a fraction eluted with ethyl acetate-hexane (1:9 to1:0) was concentrated under reduced pressure to give the object product(105 mg).

MS (ESI+, m/e) 567 (M+1)

Reference Example 155 tert-butyl(3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(1H-1,2,4-triazol-1-ylmethyl)piperidine-1-carboxylate

A solution of tert-butyl(3R,5S)-3-(hydroxymethyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate(208 mg), 1,3,4-triazole (52 mg), triphenylphosphine (262 mg) anddiisopropyl azodicarboxylate (40% toluene solution, 632 mg) in THF (5ml) was stirred at 50° C. for 15 hr. The reaction mixture wasconcentrated under reduced pressure, diluted with water and ethylacetate, and the organic layer was separated. The organic layer waswashed with saturated brine, and dried over anhydrous sodium sulfate.The solvent was evaporated under reduced pressure. The residue wassubjected to silica gel column chromatography, and a fraction elutedwith ethyl acetate-hexane (1:5-1:0) and ethyl acetate-methanol (1:0-9:1)was concentrated under reduced pressure. The residue was subjected tobasic silica gel column chromatography, and a fraction eluted with ethylacetate-hexane (1:9 to 3:1) was concentrated under reduced pressure togive the object product (180 mg).

MS (ESI+, m/e) 568 (M+1)

In the same manner as in Example 60, the following compounds (Examples77-79) were obtained.

Example 771-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(1H-pyrazol-1-ylmethyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidetrihydrochloride

MS (ESI+, m/e) 467 (M+1)

Example 781-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(1H-1,2,4-triazol-1-ylmethyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 468 (M+1)

Example 79N-[(3S,5R)-5-acetylpiperidin-3-yl]-1-(4-methoxybutyl)-N-(2-methylpropyl)-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 429 (M+1)

In the same manner as in Reference Example 149, the following compound(Reference Example 156) was obtained.

Reference Example 156 tert-butyl(3S,5R)-3-[{[6-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate

In the same manner as in Reference Example 150, the following compound(Reference Example 157) was obtained.

Reference Example 157 tert-butyl(3R,5S)-3-acetyl-5-[{[6-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate

MS (ESI+, m/e) 547 (M+1)

In the same manner as in Reference Example 151, the following compound(Reference Example 158) was obtained.

Reference Example 158 tert-butyl(3S,5R)-3-[{[6-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(1-hydroxyethyl)piperidine-1-carboxylate

MS (ESI+, m/e) 549 (M+1)

In the same manner as in Example 76, the following compound (Example 80)was obtained.

Example 806-fluoro-N-[(3S,5R)-5-(1-hydroxyethyl)piperidin-3-yl]-1-(4-methoxybutyl)-N-(2-methylpropyl)-1H-benzimidazole-2-carboxamidedihydrochloride

In the same manner as in Reference Example 69, the following compounds(Reference Examples 159-160) were obtained.

Reference Example 159 1-tert-butyl3-methyl(3R,5S)-5-{[(1-ethyl-1H-benzimidazol-2-yl)carbonyl](2-methylpropyl)amino}piperidine-1,3-dicarboxylate

MS (ESI+, m/e) 487 (M+1)

Reference Example 160 1-tert-butyl3-methyl(3R,5S)-5-[{[1-(cyclopropylmethyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate

MS (ESI+, m/e) 513 (M+1)

In the same manner as in Reference Example 74, the following compounds(Reference Examples 161-162) were obtained.

Reference Example 161(3R,5S)-1-(tert-butoxycarbonyl)-5-{[(1-ethyl-1H-benzimidazol-2-yl)carbonyl](2-methylpropyl)amino}piperidine-3-carboxylicacid

MS (ESI+, m/e) 473 (M+1)

Reference Example 162(3R,5S)-1-(tert-butoxycarbonyl)-5-[{[1-(cyclopropylmethyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid

MS (ESI+, m/e) 499 (M+1)

Reference Example 163 tert-butyl(3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

(3R,5S)-1-(tert-Butoxycarbonyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid (10 g) and morpholine (1.6 g) were dissolved in DMF (100 ml),WSC.HCL (4.8 g) and HOBt (3.1 g) were added, and the mixture was stirredat 50° C. for 12 hr. The reaction mixture was poured into 10% aqueoussodium bicarbonate, and the mixture was extracted with ethyl acetate.The extracts were combined, washed with brine, and dried over anhydroussodium sulfate. The solvent was evaporated under reduced pressure. Theresidue was subjected to silica gel column chromatography, and afraction eluted with ethyl acetate-hexane (1:1-1:0) was concentratedunder reduced pressure to give the object product (8.9 g).

¹H-NMR (CDCl₃) δ 0.63-0.80 (2H, m), 0.89-1.07 (4H, m), 1.41-1.59 (9H,m), 1.59-1.80 (2H, m), 1.87-2.23 (4H, m), 2.30-2.98 (3H, m), 3.21-3.46(6H, m), 3.49-3.91 (10H, m), 3.95-4.47 (5H, m), 7.18-7.51 (3H, m),7.56-7.84 (1H, m).

MS (ESI+, m/e) 600 (M+1)

In the same manner as in Reference Example 163, the following compounds(Reference Examples 164-165) were obtained.

Reference Example 164 tert-butyl(3S,5R)-3-{[(1-ethyl-1H-benzimidazol-2-yl)carbonyl](2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 542 (M+1)

Reference Example 165 tert-butyl(3S,5R)-3-[{[1-(cyclopropylmethyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 568 (M+1)

In the same manner as in Example 60, the following compounds (Examples81-82) were obtained.

Example 811-ethyl-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 442 (M+1)

Example 821-(cyclopropylmethyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 468 (M+1)

In the same manner as in Reference Example 79, the following compound(Reference Example 166) was obtained.

Reference Example 166 tert-butyl(3S,5R)-3-{[(1-ethyl-1H-benzimidazol-2-yl)carbonyl](2-methylpropyl)amino}-5-(hydroxymethyl)piperidine-1-carboxylate

MS (ESI+, m/e) 459 (M+1)

In the same manner as in Example 76, the following compound (Example 83)was obtained.

Example 831-ethyl-N-[(3S,5R)-5-(hydroxymethyl)piperidin-3-yl]N-(2-methylpropyl)-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 359 (M+1)

Reference Example 167 tert-butyl(3S,5R)-3-[(1,3-benzothiazol-2-ylcarbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

1,3-Benzothiazole-2-carboxylic acid (29 mg),tert-butyl(3S,5R)-3-[(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(50 mg) and N,N-diisopropylethylamine (118 μl) were dissolved inacetonitrile (3 ml), chloro-N,N,N′,N′-tetramethylformamidiniumhexafluorophosphate (57 mg) was added at 0° C., and the mixture wasstirred at room temperature for 2 hr. The reaction mixture was dilutedwith 10% aqueous sodium bicarbonate, and the mixture was extracted withethyl acetate. The extract was washed with saturated brine, and driedover anhydrous sodium sulfate. The solvent was evaporated under reducedpressure. The residue was subjected to silica gel column chromatography,and a fraction eluted with ethyl acetate-hexane (1:1-1:0) wasconcentrated under reduced pressure to give the object product (58 mg).

MS (ESI+, m/e) 531 (M+1)

In the same manner as in Example 60, the following compound (Example 84)was obtained.

Example 84N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1,3-benzothiazole-2-carboxamidehydrochloride

MS (ESI+, m/e) 431 (M+1)

Example 851-(3-methoxypropyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamide½ sulfate

tert-Butyl(3S,5R)-3-{(1H-benzimidazol-2-ylcarbonyl)(2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(700 mg), 3-methoxypropan-1-ol (123 mg) and triphenylphosphine (465 mg)were dissolved in THF (20 ml), diisopropyl azodicarboxylate (40% toluenesolution: 896 mg) was added, and the mixture was stirred at roomtemperature for 60 hr. The reaction mixture was diluted with water, andthe mixture was extracted with ethyl acetate. The extract was saturatedaqueous sodium hydrogen carbonate and saturated washed with brine, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure. The residue was subjected to silica gel columnchromatography, and a fraction eluted with ethyl acetate-hexane(1:9-1:3) was concentrated under reduced pressure. The obtainedsubstance was dissolved in ethyl acetate (3 ml), 4M hydrogenchloride-ethyl acetate (3 ml) was added, and the mixture was stirred atroom temperature for 15 hr. The reaction mixture was basified withsaturated aqueous sodium hydrogen carbonate, and extracted with ethylacetate. The extract was dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was subjectedto basic silica gel column chromatography, and a fraction eluted withethyl acetate-hexane (1:9-1:0) and ethyl acetate-methanol (93:7) wasconcentrated under reduced pressure. The obtained substance wasdissolved in ethyl acetate (10 ml), sulfuric acid (42 mg) was added, andthe solvent was evaporated under reduced pressure. The residue wasdissolved in ethanol (10 ml), and the solvent was evaporated underreduced pressure. The residue was crystallized from ethylacetate-methanol to give the object product (180 mg) as crystals.

¹H-NMR (CDCl₃) δ 0.70 (2H, d), 0.94 (4H, dd), 1.69-2.28 (5H, m),2.60-2.85 (2H, m), 2.85-3.15 (3H, m), 3.15-3.25 (5H, m), 3.41-3.74 (11H,m), 3.86-4.20 (1H, m), 4.20-4.52 (2H, m), 7.18-7.48 (2H, m), 7.53-7.84(2H, m)

MS (ESI+, m/e) 486 (M+1)

Example 861-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamide½ sulfate

1-(4-Methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamide(1 g) and sulfuric acid (0.055 ml) were dissolved in ethyl acetate (30ml) and ethanol (1 ml) with heating (100° C.), and stood while graduallycooling to room temperature. The precipitate was collected byfiltration, and washed with ethyl acetate. The obtained crude crystals(0.37 g) were dissolved in ethyl acetate (3.75 ml) and ethanol (1.5 ml)with heating (70° C.), and the seed crystal was added. The mixture wasstood for 15 hr while gradually cooling to room temperature, andfiltered. The crystals were washed with ethyl acetate, and dried underreduced pressure to give the object product (0.18 g) as crystals.

¹H-NMR (DMSO-d₆) δ 0.70 (2H, d), 0.94 (4H, dd), 1.30-1.61 (2H, m), 1.78(2H, dd), 1.86-2.02 (1H, m), 2.02-2.21 (1H, m), 2.58-2.85 (2H, m),2.89-3.02 (1H, m), 3.15-3.21 (3H, m), 3.25-3.65 (17H, m), 3.98 (1H, brs), 4.19-4.53 (2H, m), 7.23-7.56 (2H, m), 7.62-8.00 (2H, m)

MS (ESI+, m/e) 500 (M+1)

Reference Example 168 tert-butyl(3S,5R)-3-[{[1-(2-methoxy-2-oxoethyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

tert-Butyl(3S,5R)-3-{(1H-benzimidazol-2-ylcarbonyl)(2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(1.06 g) was dissolved in dimethylformamide (20 ml), methyl bromoacetate(390 μl) and cesium carbonate (2.02 g) were added and the mixture wasstirred at 55° C. for 1 hr. The reaction mixture was concentrated underreduced pressure, diluted with water, and the mixture was extracted withethyl acetate. The extract was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was subjected to silica gel chromatography, and a fractioneluted with ethyl acetate-hexane (1:9)-ethyl acetate was concentratedunder reduced pressure to give the object product (1.19 g).

MS (ESI+, m/e) 586 (M+1)

Reference Example 169 tert-butyl(3S,5R)-3-[[[1-(2-hydroxyethyl)-1H-benzimidazol-2-yl]carbonyl](2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

Calcium chloride (650 mg) was suspended in ethanol (80 ml) and sodiumborohydride (740 mg) was added at 0° C. After stirring at 0° C. for 15min, a solution of tert-butyl(3S,5R)-3-[[[1-(2-methoxy-2-oxoethyl)-1H-benzimidazol-2-yl]carbonyl](2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(1.15 g) in THF (80 ml) was added dropwise. After stirring at roomtemperature for 2 hr, the reaction mixture was diluted with 10% aqueouscitric acid solution, and the mixture was extracted with ethyl acetate.The extract was washed with saturated aqueous sodium hydrogen carbonate,and dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure. The residue was subjected to silica gelchromatography, and a fraction eluted with ethyl acetate-hexane(1:9-1:0)-ethyl acetate-methanol (85:15) was concentrated under reducedpressure to give the object product (849 mg).

MS (ESI+, m/e) 558 (M+1)

In the same manner as in the method shown in Example 60, the compounddescribed in the following Example 87 was obtained.

Example 87 methyl (2-{(2-methylpropyl)[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]carbamoyl}-1H-benzimidazol-1-yl)acetatedihydrochloride

MS (ESI+, m/e) 486 (M+1)

Example 881-(2-hydroxyethyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidedihydrochloride

tert-Butyl(3S,5R)-3-[[[1-(2-hydroxyethyl)-1H-benzimidazol-2-yl]carbonyl](2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(51 mg) was dissolved in 10% hydrogen chloride-methanol (4 ml), and themixture was stirred at room temperature for 41 hr and concentrated togive the object product (44 mg).

MS (ESI+, m/e) 458 (M+1)

Example 891-(2-cyclopropylethyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidedihydrochloride

To a solution of tert-butyl(3S,5R)-3-[(1H-benzimidazol-2-ylcarbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(257 mg), 2-cyclopropylethanol (86 mg) and triphenylphosphine (263 mg)in toluene (10 ml) was added diisopropyl azodicarboxylate (506 μl) atroom temperature, and the mixture was stirred at the same temperaturefor 17 hr. The reaction mixture was diluted with aqueous sodiumbicarbonate, and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure. The residuewas subjected to basic silica gel column chromatography, and a fractioneluted with ethyl acetate was concentrated under reduced pressure togive tert-butyl(3S,5R)-3-[{[1-(2-cyclopropylethyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate.The obtained tert-butyl(3S,5R)-3-[{[1-(2-cyclopropylethyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylatewas dissolved in 4M hydrogen chloride-ethyl acetate (5 ml), and themixture was stirred at room temperature for 3 hr. The reaction mixturewas concentrated, and the residue was subjected to reversed-phasepreparative HPLC and the eluted fraction was concentrated under reducedpressure. The residue was diluted with aqueous sodium bicarbonate, andthe mixture was extracted with ethyl acetate. The extract was washedwith saturated brine, and dried over anhydrous sodium sulfate. 4MHydrogen chloride-ethyl acetate (1 ml) was added and the mixture wasstirred for 5 min. The solvent was evaporated under reduced pressure togive the object product (220 mg).

MS (ESI+, m/e) 482 (M+1)

Reference Example 170 tert-butyl(3R,5S)-3-(1H-benzimidazol-2-yl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate

(3R,5S)-1-(tert-Butoxycarbonyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid (265 mg), phenylenediamine (54 mg), 1H-benzotriazol-1-ol (95 mg)and N,N-diisopropylethylamine (259 μl) were dissolved in DMF (5 ml),WSC.HCl (144 mg) was added and the mixture was stirred at roomtemperature for 15 hr. The reaction mixture was diluted with aqueoussodium bicarbonate, and extracted with ethyl acetate. The extract waswashed successively with water and saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The residue was dissolved in acetic acid (5 ml), and themixture was stirred at 80° C. for 5 hr. The mixture was cooled to roomtemperature, and the reaction mixture was concentrated. To the residuewas added aqueous sodium bicarbonate, and the mixture was extracted withethyl acetate. The extract was washed with saturated brine, and driedover anhydrous sodium sulfate. The solvent was evaporated under reducedpressure. The residue was subjected to silica gel column chromatography,and a fraction eluted with ethyl acetate was concentrated under reducedpressure to give the object product (115 mg).

MS (ESI+, m/e) 603 (M+1)

In the same manner as in Example 12, the following compound (Example 90)was obtained.

Example 90N-[(3S,5R)-5-(1H-benzimidazol-2-yl)piperidin-3-yl]-1-(4-methoxybutyl)-N-(2-methylpropyl)-1H-benzimidazole-2-carboxamidetrihydrochloride

MS (ESI+, m/e) 503 (M+1)

Reference Example 171 1-tert-butyl 3-methyl(3R,5S)-5-[(2-methylpropyl){[1-(2-phenylethyl)-1H-benzimidazol-2-yl]carbonyl}amino]piperidine-1,3-dicarboxylate

To a solution of 1-tert-butyl3-methyl(3R,5S)-5-[(1H-benzimidazol-2-ylcarbonyl)(2-methylpropyl)amino]piperidine-1,3-dicarboxylate(1.38 g) and (2-bromoethyl)benzene (810 μl) in N,N-dimethylacetamide (30ml) was added cesium carbonate (2.93 g), and the mixture was stirred at65° C. for 15 hr. (2-Bromoethyl)benzene (810 μl) was added to thereaction mixture, and the mixture was further stirred at 65° C. for 5hr. The reaction mixture was cooled to room temperature, diluted withwater and extracted with ethyl acetate. The extract was washed withsaturated brine, and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure. The residue was subjected tosilica gel column chromatography, and a fraction eluted with ethylacetate-hexane (1:1) was concentrated under reduced pressure to give theobject product (1.40 g).

MS (ESI+, m/e) 563 (M+1)

Reference Example 172(3R,5S)-1-(tert-butoxycarbonyl)-5-[(2-methylpropyl){[1-(2-phenylethyl)-1H-benzimidazol-2-yl]carbonyl}amino]piperidine-3-carboxylicacid

1-tert-Butyl 3-methyl(3R,5S)-5-[(2-methylpropyl){[1-(2-phenylethyl)-1H-benzimidazol-2-yl]carbonyl}amino]piperidine-1,3-dicarboxylate(1.12 g) was dissolved in methanol, 2M aqueous sodium hydroxide solution(10 ml) was added dropwise at room temperature. The reaction mixture wasstirred at 50° C. for 3 hr. The reaction mixture was adjusted to pH 7with 1M hydrochloric acid, and extracted with ethyl acetate. The extractwas washed with saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure to give theobject product (1.07 g).

MS (ESI+, m/e) 549 (M+1)

In the same manner as in Reference Example 55, the following compound(Reference Example 173) was obtained.

Reference Example 173 tert-butyl (3R,5S)-3-carbamoyl-5-[(2-methylpropyl){[1-(2-phenylethyl)-1H-benzimidazol-2-yl]carbonyl}amino]piperidine-1-carboxylate

MS (ESI+, m/e) 548 (M+1)

In the same manner as in Example 12, the following compound (Example 91)was obtained.

Example 91N-[(3S,5R)-5-carbamoylpiperidin-3-yl]-N-(2-methylpropyl)-1-(2-phenylethyl)-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 448 (M+1)

In the same manner as in Reference Example 60, the following compound(Reference Example 174) was obtained.

Reference Example 174 tert-butyl(3R,5S)-3-(hydroxymethyl)-5-[(2-methylpropyl){[1-(2-phenylethyl)-1H-benzimidazol-2-yl]carbonyl}amino]piperidine-1-carboxylate

MS (ESI+, m/e) 535 (M+1)

In the same manner as in Example 24, the following compound (Example 92)was obtained.

Example 92N-[(3S,5R)-5-(hydroxymethyl)piperidin-3-yl]-N-(2-methylpropyl)-1-(2-phenylethyl)-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 435 (M+1)

Reference Example 175 tert-butyl (3S,5R)-3-{(2-methylpropyl)[(1-{2[(methylsulfonyl)oxy]ethyl}-1H-benzimidazol-2-yl)carbonyl]amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

To a solution of tert-butyl(3S,5R)-3-[[[1-(2-hydroxyethyl)-1H-benzimidazol-2-yl]carbonyl](2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(223 mg) and triethylamine (84 μl) in THF (5 ml) was added dropwisemethanesulfonyl chloride (37 μl) at room temperature. The reactionmixture was stirred at room temperature for 3 hr, diluted with aqueoussodium bicarbonate, and extracted with ethyl acetate. The extract waswashed with saturated brine, and dried over anhydrous sodium sulfate.The solvent was evaporated under reduced pressure to give the objectproduct (288 mg).

MS (ESI+, m/e) 636 (M+1)

Reference Example 176 tert-butyl(3S,5R)-3-[(2-methylpropyl)({1-[2-(1H-pyrazol-1-yl)ethyl]-1H-benzimidazol-2-yl}carbonyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

To a solution of tert-butyl (3S,5R)-3-{(2-methylpropyl)[(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-benzimidazol-2-yl)carbonyl]amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(127 mg) and pyrazole (41 mg) in N,N-dimethylacetamide (3 ml) was addedcesium carbonate (326 mg), and the mixture was stirred at 60° C. for 3days. The to reaction mixture was diluted with water, and extracted withethyl acetate. The extract was washed with saturated brine, and driedover anhydrous sodium sulfate. The solvent was evaporated under reducedpressure. The residue was subjected to silica gel column chromatography,and a fraction eluted with ethyl acetate was concentrated under reducedpressure to give the object product (72 mg).

MS (ESI+, m/e) 608 (M+1)

In the same manner as in Reference Example 176, the following compound(Reference Example 177) was obtained.

Reference Example 177 tert-butyl(3S,5R)-3-[({1-[2-(1H-imidazol-1-yl)ethyl]-1H-benzimidazol-2-yl}carbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 608 (M+1)

In the same manner as in Example 12, the following compounds (Examples93-94) were obtained.

Example 93N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1-[2-(1H-pyrazol-1-yl)ethyl]-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 508 (M+1)

Example 941-[2-(1H-imidazol-1-yl)ethyl]-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidetrihydrochloride

MS (ESI+, m/e) 508 (M+1)

In the same manner as in Example 89, the following compound (Example 95)was obtained.

Example 951-(3-cyclopropylpropyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 496 (M+1)

Example 961-(3-hydroxypropyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidedihydrochloride

To a mixed solution of tert-butyl(3S,5R)-3-[(1H-benzimidazol-2-ylcarbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(103 mg), propane-1,3-diol (152 mg) and triphenylphosphine (105 mg) intoluene (5 ml) and THF (5 ml) was added diisopropyl azodicarboxylate(202 μl) at room temperature, and the mixture was stirred at the sametemperature for 15 hr. The reaction mixture was diluted with aqueoussodium bicarbonate, and extracted with ethyl acetate. The extract waswashed with saturated brine, and dried over anhydrous sodium sulfate.The solvent was evaporated under reduced pressure. The residue wassubjected to basic silica gel column chromatography, and a fractioneluted with ethyl acetate was concentrated under reduced pressure togive tert-butyl(3S,5R)-3-[{[1-(3-hydroxypropyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate.The obtained tert-butyl(3S,5R)-3-[{[1-(3-hydroxypropyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylatewas dissolved in 10-20% hydrogen chloride-methanol (3 ml), and themixture was stirred at room temperature for 3 hr. The reaction mixturewas concentrated to give the object product (22 mg).

MS (ESI+, m/e) 472 (M+1)

Reference Example 178 tert-butyl(3S,5R)-3-[{[1-(3-ethoxy-3-oxopropyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

To a solution of tert-butyl(3S,5R)-3-[(1H-benzimidazol-2-ylcarbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(257 mg) and ethyl 3-bromopropanoate (181 mg) in N,N-dimethylacetamide(5 ml) was added cesium carbonate (489 mg), and the mixture was stirredat 70° C. for 15 hr. Ethyl 3-bromopropanoate (181 mg) was added to thereaction mixture, and the mixture was further stirred at 70° C. for 5hr. The reaction mixture was cooled to room temperature, diluted withwater, and extracted with ethyl acetate. The extract was washed withsaturated brine, and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure. The residue was subjected tosilica gel column chromatography, and a fraction eluted with ethylacetate-hexane (6:4) was concentrated under reduced pressure to give theobject product (225 mg).

MS (ESI+, m/e) 614 (M+1)

Reference Example 179 tert-butyl(3S,5R)-3-[({1-[3-(2-acetylhydrazino)-3-oxopropyl]-1H-benzimidazol-2-yl}carbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

tert-Butyl(3S,5R)-3-[{[1-(3-ethoxy-3-oxopropyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(307 mg) was dissolved in ethanol (10 ml), hydrazine monohydrate (243μl) was added and the mixture was heated under reflux for 6 hr withstirring. The reaction mixture was concentrated, ethyl acetate was addedto the residue, and the mixture was washed with saturated brine, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure. The residue was dissolved in THF (5 ml), andtriethylamine (209 μl) was added. The reaction mixture was cooled to 0°C., acetic anhydride (71 μl) was added dropwise and the mixture wasstirred at room temperature for 15 hr. The reaction mixture was dilutedwith aqueous sodium bicarbonate, and extracted with ethyl acetate. Theextract was washed with saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure to give theobject product (292 mg).

MS (ESI+, m/e) 642 (M+1)

Reference Example 180 tert-butyl(3S,5R)-3-[({1-[2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]-1H-benzimidazol-2-yl}carbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

tert-Butyl(3S,5R)-3-[({1-[3-(2-acetylhydrazino)-3-oxopropyl]-1H-benzimidazol-2-yl}carbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(292 mg) was dissolved in pyridine (5 ml), and trifluoromethanesulfonicanhydride (2301) was added dropwise at room temperature. The reactionmixture was stirred at room temperature for 15 hr, and concentrated. Theresidue was diluted with 10% aqueous citric acid solution, and themixture was extracted with ethyl acetate. The extract was washed withaqueous sodium bicarbonate and saturated brine, and dried over anhydroussodium sulfate. The solvent was evaporated under reduced pressure. Theresidue was subjected to silica gel column chromatography, and afraction eluted with ethyl acetate was concentrated under reducedpressure to give the object product (117 mg).

MS (ESI+, m/e) 624 (M+1)

In the same manner as in Example 23, the following compound (Example 97)was obtained.

Example 971-[2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamide

MS (ESI+, m/e) 524 (M+1)

Reference Example 1813-(2-{[(3S,5R)-1-(tert-butoxycarbonyl)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl](2-methylpropyl)carbamoyl}-1H-benzimidazol-1-yl)propanoicacid

To a solution of tert-butyl(3S,5R)-3-[{[1-(3-ethoxy-3-oxopropyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(225 mg) in ethanol (5 ml) was added 2M aqueous sodium hydroxidesolution, and the mixture was stirred at room temperature for 3 days.The reaction mixture was adjusted to pH 7 with 1M hydrochloric acid, andextracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure to give the object product (215 mg).

MS (ESI+, m/e) 586 (M+1)

Reference Example 182 tert-butyl(3S,5R)-3-[{[1-(3-amino-3-oxopropyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

3-(2-{[(3S,5R)-1-(tert-Butoxycarbonyl)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl](2-methylpropyl)carbamoyl}-1H-benzimidazol-1-yl)propanoicacid (215 mg) and 1H-1,2,3-benzotriazol-1-ol ammonium salt (84 mg) weredissolved in DMF (5 ml), WSC.HCl (142 mg) was added and the mixture wasstirred at room temperature for 15 hr. The reaction mixture wasconcentrated under reduced pressure, and the residue was diluted with10% aqueous citric acid solution and extracted with ethyl acetate. Theextract was washed with aqueous sodium bicarbonate and saturated brine,and dried over anhydrous sodium sulfate. The solvent was evaporatedunder reduced pressure. The residue was subjected to silica gel columnchromatography, and a fraction eluted with ethyl acetate wasconcentrated under reduced pressure to give the object product (199 mg).

MS (ESI+, m/e) 585 (M+1)

Reference Example 183 tert-butyl(3S,5R)-3-[{[1-(2-cyanoethyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

tert-Butyl(3S,5R)-3-[{[1-(3-amino-3-oxopropyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(233 mg) was dissolved in pyridine (5 ml), trifluoroacetic anhydride(116 μl) was added at 0° C. and the mixture was stirred at roomtemperature for 2 hr. The reaction mixture was concentrated underreduced pressure, and diluted with ethyl acetate. 1M Hydrochloric acidwas added, and the mixture was extracted with ethyl acetate. The extractwas washed with aqueous sodium bicarbonate and saturated brine, driedover anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was subjected to silica gel chromatography, and afraction eluted with ethyl acetate-hexane (7:3) was concentrated underreduced pressure to give the object product (197 mg).

MS (ESI+, m/e) 567 (M+1)

Example 98N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1-[2-(1,2,4-oxadiazol-3-yl)ethyl]-1H-benzimidazole-2-carboxamidedihydrochloride

Hydroxylamine hydrochloride (125 mg) was dissolved in dimethyl sulfoxide(5 ml), sodium hydrogen carbonate (463 mg) was added and the mixture wasstirred at 50° C. for 1 hr. A solution of tert-butyl(3S,5R)-3-[{[1-(2-cyanoethyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(100 mg) in dimethyl sulfoxide (5 ml) was added to the reaction mixture,and the mixture was stirred at 90° C. for 3 hr. The reaction mixture wasallowed to cool to room temperature, diluted with water, and extractedwith ethyl acetate. The extract was washed with saturated brine, driedover anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was dissolved in trimethyl orthoformate (5 ml) andthe mixture was stirred at 100° C. for 5 hr. The reaction mixture wasconcentrated under reduced pressure, and the residue was subjected tobasic silica gel chromatography, and a fraction eluted with ethylacetate was concentrated under reduced pressure to give tert-butyl(3S,5R)-3-[(2-methylpropyl)({1-[2-(1,2,4-oxadiazol-3-yl)ethyl]-1H-benzimidazol-2-yl}carbonyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate.The obtained tert-butyl(3S,5R)-3-[(2-methylpropyl)({1-[2-(1,2,4-oxadiazol-3-yl)ethyl]-1H-benzimidazol-2-yl}carbonyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylatewas dissolved in 4M hydrogen chloride-ethyl acetate (3 ml), and themixture was stirred at room temperature for 2 hr. The reaction mixturewas concentrated, and the residue was subjected to reversed-phasepreparative HPLC and the eluted fraction was concentrated under reducedpressure. The residue was diluted with aqueous sodium bicarbonate, andthe mixture was extracted with ethyl acetate. The extract was washedwith saturated brine, and dried over anhydrous sodium sulfate. 4MHydrogen chloride-ethyl acetate (1 ml) was added and the mixture wasstirred for min. The solvent was evaporated under reduced pressure togive the object product (35 mg).

MS (ESI+, m/e) 510 (M+1)

Reference Example 184 tert-butyl(3S,5R)-3-[({1-[2-(ethenyloxy)ethyl]-1H-benzimidazol-2-yl}carbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

To a solution of tert-butyl(3S,5R)-3-{(1H-benzimidazol-2-ylcarbonyl)(2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(308 mg), (2-chloroethoxy)ethene (192 mg) and potassium iodide (5 mg) inN,N-dimethylacetamide (5 ml) was added cesium carbonate (586 mg), andthe mixture was stirred at 60° C. for 15 hr. The reaction mixture wascooled to room temperature, diluted with water, and extracted with ethylacetate. The extract was washed with saturated brine, and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure. The residue was subjected to silica gel column chromatography,and a fraction eluted with ethyl acetate-hexane (6:4) was concentratedunder reduced pressure to give the object product (323 mg).

MS (ESI+, m/e) 584 (M+1)

Example 991-[2-(cyclopropyloxy)ethyl]-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidedihydrochloride

To a solution of tert-butyl(3S,5R)-3-[({1-[2-(ethenyloxy)ethyl]-1H-benzimidazol-2-yl}carbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(323 mg) and 1M diethylzinc-hexane solution (2.5 ml) in dichloromethane(5 ml) was added dropwise diiodomethane (443 μl) at room temperatureover 5 min, and the mixture was stirred at room temperature for 3 hr.The reaction mixture was diluted with 1M hydrochloric acid, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure. The residue was dissolved inmethanol (5 ml), 4M hydrogen chloride-ethyl acetate (5 ml) was added andthe mixture was stirred at room temperature for 5 hr. The reactionmixture was concentrated, and the residue was subjected toreversed-phase preparative HPLC and the eluted fraction was concentratedunder reduced pressure. The residue was diluted with aqueous sodiumbicarbonate, and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, and dried over anhydrous sodiumsulfate. 4M Hydrogen chloride-ethyl acetate (1 ml) was added and themixture was stirred for 5 min. The solvent was evaporated under reducedpressure to give the object product (35 mg).

MS (ESI+, m/e) 498 (M+1)

Reference Example 185 tert-butyl(3S,5R)-3-[{[1-(5-hydroxypentyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

To a mixed solution of tert-butyl(3S,5R)-3-[(1H-benzimidazol-2-ylcarbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(308 mg), pentane-1,5-diol (1.25 g) and triphenylphosphine (472 mg) intoluene (10 ml)-THF (10 ml) was added diisopropyl azodicarboxylate (910μl) at room temperature, and the mixture was stirred at the sametemperature for 15 hr. The reaction mixture was diluted with aqueoussodium bicarbonate, and the mixture was extracted with ethyl acetate.The extract was washed with saturated brine, and dried over anhydroussodium sulfate. The solvent was evaporated under reduced pressure. Theresidue was subjected to silica gel column chromatography, and afraction eluted with ethyl acetate was concentrated under reducedpressure to give the object product (250 mg).

MS (ESI+, m/e) 600 (M+1)

Example 1001-(5-hydroxypentyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidedihydrochloride

tert-Butyl(3S,5R)-3-[{[1-(5-hydroxypentyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(100 mg) was dissolved in 10-20% hydrogen chloride-methanol (5 ml), andthe mixture was stirred at room temperature for 15 hr. The reactionmixture was concentrated, and the residue was subjected toreversed-phase preparative HPLC and the eluted fraction was concentratedunder reduced pressure. The residue was diluted with aqueous sodiumbicarbonate, and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, and dried over anhydrous sodiumsulfate. 10-20% Hydrogen chloride-methanol (3 ml) was added and themixture was stirred for 5 min. The solvent was evaporated under reducedpressure to give the object product (34 mg).

MS (ESI+, m/e) 500 (M+1)

Reference Example 186 tert-butyl(3S,5R)-3-[{[1-(5-methoxypentyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

To a solution of tert-butyl(3S,5R)-3-[{[1-(5-hydroxypentyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(150 mg) and triethylamine (701) in tetrahydrofuran (5 ml) was addedmethanesulfonyl chloride (725 μl) at 0° C., and the mixture was stirredat room temperature for 2 hr. Aqueous sodium bicarbonate was added tothe reaction mixture, and the mixture was extracted with ethyl acetate.The extract was washed with saturated brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas dissolved in methanol (5 ml), 28% sodium methoxide-methanol solution(482 mg) was added at room temperature and the mixture was stirred at60° C. for 3 days. The reaction mixture was diluted with aqueous sodiumbicarbonate, and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure. The residuewas subjected to silica gel column chromatography, and a fraction elutedwith ethyl acetate was concentrated under reduced pressure to give theobject product (123 mg).

MS (ESI+, m/e) 614 (M+1)

Example 1011-(5-methoxypentyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidedihydrochloride

tert-Butyl(3S,5R)-3-[{[1-(5-methoxypentyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(123 mg) was dissolved in 4M hydrogen chloride-ethyl acetate (5 ml), andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was concentrated, and the residue was subjected toreversed-phase preparative HPLC and the eluted fraction was concentratedunder reduced pressure. The residue was diluted with aqueous sodiumbicarbonate, and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, and dried over anhydrous sodiumsulfate. 4M Hydrogen chloride-ethyl acetate (1 ml) was added and themixture was stirred for 5 min. The solvent was evaporated under reducedpressure to give the object product (76 mg).

MS (ESI+, m/e) 514 (M+1)

In the same manner as in Reference Example 168, the following compound(Reference Example 187) was obtained.

Reference Example 187 tert-butyl(3S,5R)-3-[{[1-(4-ethoxy-4-oxobutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 628 (M+1)

In the same manner as in Reference Example 169, the following compound(Reference Example 188) was obtained.

Reference Example 188 tert-butyl(3S,5R)-3-[{[1-(4-hydroxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 586 (M+1)

In the same manner as in Example 100, the following compound (Example102) was obtained.

Example 1021-(4-hydroxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 486 (M+1)

Example 103 1-(4-methoxybutyl)-N-[(3S,5R)-5-(3-methyl-,2,4-oxadiazol-5-yl)piperidin-3-yl]-N-(2-methylpropyl)-1H-benzimidazole-2-carboxamidedihydrochloride

(3R,5S)-1-(tert-Butoxycarbonyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid (265 mg), N-hydroxy acetamidine (56 mg), 1H-benzotriazol-1-ol (95mg) and N,N-diisopropylethylamine (259 μl)) were dissolved in DMF (10ml), WSC.HCl (144 mg) was added and the mixture was stirred at roomtemperature for 15 hr. The reaction mixture was concentrated underreduced pressure, and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The residue was dissolved in toluene (15 ml), and the mixture wasrefluxed under heating for 15 hr. The reaction mixture was cooled toroom temperature, and concentrated under reduced pressure. The residuewas subjected to silica gel column chromatography, and a fraction elutedwith ethyl acetate-hexane (1:1) was concentrated under reduced pressureto give tert-butyl(3S,5R)-3-{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(3-methyl-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate(324 mg). The obtained tert-butyl(3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(3-methyl-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylatewas dissolved in 4M hydrogen chloride-ethyl acetate (5 ml), and themixture was stirred at room temperature for 3 hr. The reaction mixturewas concentrated, and the residue was diluted with aqueous sodiumbicarbonate, and extracted with ethyl acetate. The extract was washedwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was subjectedto basic silica gel column chromatography, and a fraction eluted withethyl acetate was concentrated under reduced pressure. The residue wasdissolved in methanol (3 ml), 4M Hydrogen chloride-ethyl acetate (1 ml)was added and the mixture was stirred for 5 min. The solvent wasevaporated under reduced pressure to give the object product (74 mg).

MS (ESI+, m/e) 469 (M+1)

In the same manner as in Example 12, the following compound (Example104) was obtained.

Example 104N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 414 (M+1)

Reference Example 189 tert-butyl(3S,5R)-3-{[(1-methyl-1H-benzimidazol-2-yl)carbonyl](2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

tert-Butyl(3S,5R)-3-{(1H-benzimidazol-2-ylcarbonyl)(2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(205 mg) was dissolved in dimethylformamide (5 ml), methyl iodide (75μl) and cesium carbonate (391 mg) were added and the mixture was stirredat room temperature for 2 hr. The reaction mixture was concentratedunder reduced pressure, diluted with aqueous sodium bicarbonate, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was subjected to silicagel chromatography, and a fraction eluted with ethyl acetate-hexane(6:4) was concentrated under reduced pressure to give the object product(184 mg).

MS (ESI+, m/e) 528 (M+1)

In the same manner as in Example 12, the following compound (Example105) was obtained.

Example 1051-methyl-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 428 (M+1)

Reference Example 190 tert-butyl(3S,5R)-3-[({1-[2-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]-1H-benzimidazol-2-yl}carbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

To a solution of tert-butyl(3S,5R)-3-[{[1-(3-ethoxy-3-oxopropyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(260 mg) in ethanol (5 ml) was added 2M aqueous sodium hydroxidesolution (1.06 ml), and the mixture was stirred at room temperature for3 days. The reaction mixture was adjusted to pH 7 with 1M hydrochloricacid, and extracted with ethyl acetate. The extract was washed withsaturated brine, and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure. The residue, N-hydroxyacetamidine (47 mg), 1H-benzotriazol-1-ol (79 mg) andN,N-diisopropylethylamine (217 μl) were dissolved in DMF (5 ml), WSC.HCl(121 mg) was added and the mixture was stirred at 60° C. for 2 hr. Thereaction mixture was concentrated under reduced pressure, and theresidue was diluted with aqueous sodium bicarbonate and extracted withethyl acetate. The extract was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The residue was dissolved in toluene (15 ml), and themixture was refluxed under heating for 15 hr. The reaction mixture wascooled to room temperature, and concentrated under reduced pressure. Theresidue was subjected to basic silica gel column chromatography, and afraction eluted with ethyl acetate-hexane (7:3) was concentrated underreduced pressure to give the object product (191 mg).

MS (ESI+, m/e) 624 (M+1)

In the same manner as in Example 12, the following compound (Example106) was obtained.

Example 1061-[2-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 524 (M+1)

In the same manner as in Reference Example 69, the following compound(Reference Example 191) was obtained.

Reference Example 191 1-tert-butyl3-methyl(3R,5S)-5-[{[1-(2,2-difluoroethyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate

MS (ESI+, m/e) 523 (M+1)

In the same manner as in Reference Example 172, the following compound(Reference Example 192) was obtained.

Reference Example 192(3R,5S)-1-(tert-butoxycarbonyl)-5-[{[1-(2,2-difluoroethyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid

MS (ESI+, m/e) 509 (M+1)

In the same manner as in Reference Example 39, the following compounds(Reference Examples 193-194) were obtained.

Reference Example 193 tert-butyl(3S,5R)-3-[{[1-(2,2-difluoroethyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 578 (M+1)

Reference Example 194 tert-butyl(3S,5R)-3-[{[1-(2,2-difluoroethyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(piperidin-1-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 576 (M+1)

In the same manner as in Example 12, the following compounds (Examples107-108) were obtained.

Example 1071-(2,2-difluoroethyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 478 (M+1)

Example 1081-(2,2-difluoroethyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(piperidin-1-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 476 (M+1)

In the same manner as in Reference Example 60, the following compound(Reference Example 195) was obtained.

Reference Example 195 tert-butyl(3S,5R)-3-[{[1-(2,2-difluoroethyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(hydroxymethyl)piperidine-1-carboxylate

MS (ESI+, m/e) 495 (M+1)

In the same manner as in Example 24, the following compound (Example109) was obtained.

Example 1091-(2,2-difluoroethyl)-N-[(3S,5R)-5-(hydroxymethyl)piperidin-3-yl]-N-(2-methylpropyl)-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 395 (M+1)

In the same manner as in Reference Example 69, the following compounds(Reference Examples 196-197) were obtained.

Reference Example 196 1-tert-butyl3-methyl(3R,5S)-5-[{[1-(1-methylethyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate

MS (ESI+, m/e) 501 (M+1)

Reference Example 197 1-tert-butyl3-methyl(3R,5S)-5-{(2-methylpropyl)[(1-propyl-1H-benzimidazol-2-yl)carbonyl]amino}piperidine-1,3-dicarboxylate

MS (ESI+, m/e) 501 (M+1)

In the same manner as in Reference Example 189, the following compound(Reference Example 198) was obtained.

Reference Example 198 1-tert-butyl 3-methyl(3R,5S)-5-[(2-methylpropyl){[1-(2,2,2-trifluoroethyl)-1H-benzimidazol-2-yl]carbonyl}amino]piperidine-1,3-dicarboxylate

MS (ESI+, m/e) 541 (M+1)

In the same manner as in Reference Example 172, the following compounds(Reference Examples 199-201) were obtained.

Reference Example 199(3R,5S)-1-(tert-butoxycarbonyl)-5-[{[1-(1-methylethyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid

MS (ESI+, m/e) 487 (M+1)

Reference Example 200(3R,5S)-1-(tert-butoxycarbonyl)-5-{(2-methylpropyl)[(1-propyl-1H-benzimidazol-2-yl)carbonyl]amino}piperidine-3-carboxylicacid

MS (ESI+, m/e) 487 (M+1)

Reference Example 201(3R,5S)-1-(tert-butoxycarbonyl)-5-[(2-methylpropyl){[1-(2,2,2-trifluoroethyl)-1H-benzimidazol-2-yl]carbonyl}amino]piperidine-3-carboxylicacid

MS (ESI+, m/e) 527 (M+1)

In the same manner as in Reference Example 39, the following compounds(Reference Examples 202-204) were obtained.

Reference Example 202 tert-butyl(3S,5R)-3-[{[1-(1-methylethyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 556 (M+1)

Reference Example 203 tert-butyl (3S,5R)-3-{(2-methylpropyl)[(1-propyl-1H-benzimidazol-2-yl)carbonyl]amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 556 (M+1)

Reference Example 204 tert-butyl (3S,5R)-3-[(2-methylpropyl){[1-(2,2,2-trifluoroethyl)-1H-benzimidazol-2-yl]carbonyl}amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 596 (M+1)

In the same manner as in Example 12, the following compounds (Examples110-112) were obtained.

Example 1101-(1-methylethyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 456 (M+1)

Example 111N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1-propyl-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 456 (M+1)

Example 112N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1-(2,2,2-trifluoroethyl)-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 496 (M+1)

In the same manner as in Reference Example 60, the following compounds(Reference Examples 205-206) were obtained.

Reference Example 205 tert-butyl(3R,5S)-3-(hydroxymethyl)-5-{(2-methylpropyl)[(1-propyl-1H-benzimidazol-2-yl)carbonyl]amino}piperidine-1-carboxylate

MS (ESI+, m/e) 473 (M+1)

Reference Example 206 tert-butyl(3R,5S)-3-(hydroxymethyl)-5-[(2-methylpropyl){[1-(2,2,2-trifluoroethyl)-1H-benzimidazol-2-yl]carbonyl}amino]piperidine-1-carboxylate

MS (ESI+, m/e) 513 (M+1)

In the same manner as in Example 24, the following compounds (Examples113-114) were obtained.

Example 113N-[(3S,5R)-5-(hydroxymethyl)piperidin-3-yl]-N-(2-methylpropyl)-1-propyl-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 373 (M+1)

Example 114N-[(3S,5R)-5-(hydroxymethyl)piperidin-3-yl]-N-(2-methylpropyl)-1-(2,2,2-trifluoroethyl)-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 413 (M+1)

In the same manner as in Reference Example 35, the following compound(Reference Example 207) was obtained.

Reference Example 207 1-cyclopropyl-2-(trichloromethyl)-1H-benzimidazole

¹H-NMR (CDCl₃) δ 1.33-1.42 (2H, m), 1.44-1.54 (2H, m), 3.51-3.61 (1H,m), 7.29-7.43 (2H, m), 7.62-7.68 (1H, m), 7.83-7.90 (1H, m).

In the same manner as in Reference Example 37, the following compound(Reference Example 208) was obtained.

Reference Example 208 1-tert-butyl3-methyl(3R,5S)-5-{[(1-cyclopropyl-1H-benzimidazol-2-yl)carbonyl](2-methylpropyl)amino}piperidine-1,3-dicarboxylate

MS (ESI+, m/e) 499 (M+1)

In the same manner as in Reference Example 172, the following compound(Reference Example 209) was obtained.

Reference Example 209(3R,5S)-1-(tert-butoxycarbonyl)-5-{[(1-cyclopropyl-1H-benzimidazol-2-yl)carbonyl](2-methylpropyl)amino}piperidine-3-carboxylicacid

MS (ESI+, m/e) 485 (M+1)

In the same manner as in Reference Example 39, the following compound(Reference Example 210) was obtained.

Reference Example 210 tert-butyl(3S,5R)-3-{[(1-cyclopropyl-1H-benzimidazol-2-yl)carbonyl](2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 554 (M+1)

In the same manner as in Example 12, the following compound (Example115) was obtained.

Example 1151-cyclopropyl-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 454 (M+1)

Reference Example 211 ethyl3-(2-phenylethyl)imidazo[1,2-a]pyridine-2-carboxylate

To a solution of ethyl 3-bromo-2-oxo-5-phenylpentanoate (1.9 g) in THF(10 ml) was added 2-aminopyridine (600 mg) at room temperature, and thereaction mixture was heated under reflux for 15 hr. The precipitatedcrystals were collected by filtration, washed with THF to give2-amino-1-[3-ethoxy-2,3-dioxo-1-(2-phenylethyl)propyl]pyridinium bromide(1.36 g).2-Amino-1-[3-ethoxy-2,3-dioxo-1-(2-phenylethyl)propyl]pyridinium bromide(1.36 g) was dissolved in ethanol (10 ml), and the mixture was refluxedunder heating for 3 hr. The reaction mixture was concentrated, anddissolved in dichloromethane. The solution was washed successively withaqueous sodium bicarbonate and saturated brine, and dried over anhydroussodium sulfate. The solvent was evaporated under reduced pressure. Theresidue was recrystallized from ethyl acetate-diethyl ether to give theobject product (950 mg).

¹H-NMR (CDCl₃) δ 1.47 (3H, t), 3.00 (2H, t), 3.57 (2H, t), 4.47 (2H, q),6.73 (1H, t), 7.12-7.13 (2H, m), 7.16-7.27 (4H, m), 7.65-7.67 (2H, m).

Reference Example 212 ethyl3-(hydroxymethyl)imidazo[1,2-a]pyridine-2-carboxylate

To a solution of ethyl imidazo[1,2-a]pyridine-2-carboxylate (5.0 g) inacetic acid (30 ml) were added 37% formaldehyde (14 ml) and sodiumacetate (8.0 g) at room temperature, and the reaction mixture was heatedunder reflux for 15 hr. The reaction mixture was cooled to roomtemperature and dissolved in dichloromethane. The mixture was adjustedto pH 8 with 10% aqueous sodium hydroxide solution at 0° C. The organiclayer was separated, washed with water and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure. The residuewas subjected to silica gel column chromatography, and a fraction elutedwith dichloromethane-methanol (15:1) was concentrated under reducedpressure to give the object product (2.1 g).

¹H-NMR (CDCl₃) δ 1.43 (3H, t), 4.42 (2H, t), 5.30 (2H, s), 7.06 (1H, t),7.45 (1H, t), 7.60 (1H, d), 8.50 (1H, d).

Reference Example 213 ethyl3-(chloromethyl)imidazo[1,2-a]pyridine-2-carboxylate hydrochloride

To a solution of ethyl3-(hydroxymethyl)imidazo[1,2-a]pyridine-2-carboxylate (2.85 g) inchloroform (40 ml) was added thionyl chloride (8.0 ml) at roomtemperature, and the mixture was heated under reflux for 12 hr. Thereaction solution was cooled to room temperature, and concentrated underreduced pressure. The precipitated crystals were collected byfiltration, washed with diethyl ether to give the object product (3.50g).

¹H-NMR (CDCl₃) δ 1.37 (3H, t), 4.40 (2H, t), 5.57 (2H, s), 7.34 (1H, t),7.67 (1H, t), 7.82 (1H, m), 8.71 (1H, d).

Reference Example 214 ethyl3-(phenoxymethyl)imidazo[1,2-a]pyridine-2-carboxylate

A solution of a mixture of phenol (2.20 g) and sodium hydride (95 wt %,500 mg) in DMF (40 ml) was added dropwise to a solution of ethyl3-(chloromethyl)imidazo[1,2-a]pyridine-2-carboxylate hydrochloride (3.5g) in DMF (50 ml) at 0° C. Triethylamine (2.7 ml) was added at the sametemperature over min. The reaction mixture was stirred at 50° C. for 3hr, and the reaction mixture was diluted with water and extracted withethyl acetate. The extract was washed with saturated brine, and driedover anhydrous sodium sulfate. The solvent was evaporated under reducedpressure. The residue was subjected to silica gel column chromatography,and a fraction eluted with ethyl acetate-hexane (6:1) was concentratedunder reduced pressure to give the object product (1.5 g).

¹H-NMR (CDCl₃) δ 1.31 (3H, t), 4.34 (2H, t), 5.80 (2H, s), 6.97 (1H, t),7.06-7.08 (2H, m), 7.12 (1H, t), 7.29-7.33 (2H, m), 7.44-7.48 (1H, m),7.70 (1H, d), 8.54 (1H, d).

Reference Example 215 ethyl3-[(1E)-4-methoxybut-1-en-1-yl]imidazo[1,2-a]pyridine-2-carboxylate

To a suspension of (3-methoxypropyl)(triphenyl)phosphonium bromide (3.56g) in THF (50 ml) was added potassium tert-butoxide (0.38 g) at −78° C.,and the mixture was stirred at the same temperature for 30 min. Ethyl3-formylimidazo[1,2-a]pyridine-2-carboxylate (1.7 g) was added to thereaction mixture, and the mixture was stirred at room temperature for 12hr. Water was added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. The residue was subjected to silicagel column chromatography, and a fraction eluted with ethyl acetate wasconcentrated under reduced pressure to give the object product (256 mg).

MS (ESI+, m/e) 275 (M+1)

Reference Example 216 ethyl3-(4-methoxybutyl)imidazo[1,2-a]pyridine-2-carboxylate

Ethyl3-[(1E)-4-methoxybut-1-en-1-yl]imidazo[1,2-a]pyridine-2-carboxylate (530mg) and diphenyl sulfide (3.6 mg) were dissolved in ethyl acetate (13ml), 10% palladium carbon (50% in water) (53 mg) was added and themixture was stirred in a hydrogen stream at ambient temperature andnormal pressure for 2.5 hr. The catalyst was filtered off, and thefiltrate was concentrated under reduced pressure. The residue wassubjected to silica gel column chromatography, and a fraction elutedwith ethyl acetate was concentrated under reduced pressure to give theobject product (260 mg).

¹H-NMR (CDCl₃) δ 1.46 (3H, t), 1.67-1.78 (4H, m), 3.32-3.34 (2H, m),3.33 (3H, s), 3.42 (2H, t), 4.46 (2H, q), 6.88 (1H, t), 7.22 (1H, dd),7.67 (1H, d), 7.99 (1H, d).

Reference Example 217 ethyl3-(4-methoxybutyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylate

Ethyl3-[(1E)-4-methoxybut-1-en-1-yl]imidazo[1,2-a]pyridine-2-carboxylate(1.40 g) was dissolved in ethyl acetate (30 ml), 10% palladium carbon(50% in water) (510 mg) was added and the mixture was stirred in ahydrogen stream at ambient temperature and normal pressure for 12 hr.The catalyst was filtered off, and the filtrate was concentrated underreduced pressure. The residue was subjected to silica gel columnchromatography, and a fraction eluted with ethyl acetate-methanol (5:1)was concentrated under reduced pressure to give the object product (1.14g).

¹H-NMR (CDCl₃) δ 1.39 (3H, t), 1.62-1.67 (4H, m), 1.89-1.92 (2H, m),1.99-2.01 (2H, m), 2.89 (2H, t), 2.92-2.96 (2H, m), 3.32 (3H, s),3.38-3.41 (2H, m), 3.82-3.85 (2H, m), 4.35 (2H, q).

Reference Example 218 tert-butyl(3S,5R)-3-[(2-methylpropyl){[3-(2-phenylethyl)imidazo[1,2-a]pyridin-2-yl]carbonyl}amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

Ethyl 3-(2-phenylethyl)imidazo[1,2-a]pyridine-2-carboxylate (883 mg) wasdissolved in ethanol (50 ml), 2N aqueous sodium hydroxide solution (3ml) was added, and the mixture was stirred at room temperature for 15hr. The reaction mixture was concentrated under reduced pressure,neutralized with 1N hydrochloric acid, subjected to DIAIONHP-(manufactured by Mitsubishi Chemical), and washed with water. Thefraction eluted with acetone was concentrated under reduced pressure togive 3-(2-phenylethyl)imidazo[1,2-a]pyridine-2-carboxylic acid (1.03 g).The obtained 3-(2-phenylethyl)imidazo[1,2-a]pyridine-2-carboxylic acid(341 mg), tert-butyl(3S,5R)-3-[(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(370 mg) and N,N-diisopropylethylamine (862 μl) were dissolved inacetonitrile (20 ml), chloro-N,N,N′,N′-tetramethylformamidiniumhexafluorophosphate (561 mg) was added and the mixture was stirred atroom temperature for 15 hr. The reaction mixture was concentrated, andthe residue was diluted with aqueous sodium bicarbonate. The mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. The residue was subjected to basicsilica gel column chromatography, and a fraction eluted with ethylacetate-hexane (9:1) was concentrated under reduced pressure to give theobject product (522 mg).

MS (ESI+, m/e) 618 (M+1)

Reference Example 219 tert-butyl (3S,5R)-3-[(2-methylpropyl){[3-(phenoxymethyl)imidazo[1,2-a]pyridin-2-yl]carbonyl}amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

Ethyl 3-(phenoxymethyl)imidazo[1,2-a]pyridine-2-carboxylate (889 mg) wasdissolved in ethanol (50 ml), 2N aqueous sodium hydroxide solution (3ml) was added, and the mixture was stirred at room temperature for 15hr. The precipitated crystals were collected by filtration, and washedwith ethanol to give sodium3-(phenoxymethyl)imidazo[1,2-a]pyridine-2-carboxylate (680 g). Theobtained sodium 3-(phenoxymethyl)imidazo[1,2-a]pyridine-2-carboxylate(290 mg), tert-butyl(3S,5R)-3-[(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(370 mg) and N,N-diisopropylethylamine (862 μl) were dissolved inacetonitrile (20 ml), chloro-N,N,N′,N′-tetramethylformamidiniumhexafluorophosphate (561 mg) was added and the mixture was stirred atroom temperature for 15 hr. The reaction mixture was concentrated, andthe residue was diluted with aqueous sodium bicarbonate, and extractedwith ethyl acetate. The extract was washed with saturated brine, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure. The residue was subjected to basic silica gel columnchromatography, and a fraction eluted with ethyl acetate-hexane (9:1)was concentrated under reduced pressure to give the object product (563mg).

¹H-NMR (CDCl₃) δ 0.65-1.06 (6H, m), 1.15-1.54 (9H, m), 1.72-2.53 (4H,m), 2.57-3.01 (2H, m), 3.16-5.00 (12H, m), 5.51-5.73 (2H, m), 6.86-7.07(4H, m), 7.23-7.35 (4H, m), 7.45-7.66 (1H, m), 8.27 (1H, t).

MS (ESI+, m/e) 620 (M+1)

In the same manner as in Example 12, the following compound (Example116) was obtained.

Example 116N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-3-(2-phenylethyl)imidazo[1,2-a]pyridine-2-carboxamidedihydrochloride

MS (ESI+, m/e) 518 (M+1)

Example 117N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-3-(phenoxymethyl)imidazo[1,2-a]pyridine-2-carboxamidedihydrochloride

tert-Butyl (3S,5R)-3-[(2-methylpropyl){[3-(phenoxymethyl)imidazo[1,2-a]pyridin-2-yl]carbonyl}amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(290 mg) was dissolved in 4M hydrogen chloride-ethyl acetate (5 ml), andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was concentrated to give the object product (278 mg).

¹H-NMR (DMSO-d₆) δ 0.63-0.97 (6H, m), 1.74-2.45 (3H, m), 2.81-4.66 (17H,m), 5.51-5.61 (2H, m), 6.95-7.11 (3H, m), 7.19-7.38 (3H, m), 7.56-7.81(2H, m), 8.57-8.69 (1H, m), 9.07-9.69 (2H, m).

MS (ESI+, m/e) 520 (M+1)

Reference Example 220 tert-butyl(3S,5R)-3-[{[3-(4-methoxybutyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

Ethyl3-(4-methoxybutyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylate(56 mg) was dissolved in ethanol (5 ml), lithium hydroxide monohydrate(42 mg) was added and the mixture was stirred at 50° C. for 6 hr. 8NAqueous sodium hydroxide solution (0.1 ml) was added to the reactionmixture, and the mixture was stirred at 60° C. for 15 hr, andconcentrated under reduced pressure. The residue was dissolved inacetonitrile (5 ml), tert-butyl(3S,5R)-3-[(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(74 mg), N,N-diisopropylethylamine (172 μl) andchloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (112 mg)were added and the mixture was stirred at room temperature for 5 hr. Thereaction mixture was concentrated, and the residue was diluted withaqueous sodium bicarbonate, and extracted with ethyl acetate. Theextract was washed with saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure. The residuewas subjected to basic silica gel column chromatography, and a fractioneluted with ethyl acetate was concentrated under reduced pressure togive the object product (26 mg).

MS (ESI+, m/e) 604 (M+1)

In the same manner as in Example 12, the following compound (Example118) was obtained.

Example 1183-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamidedihydrochloride

MS (ESI+, m/e) 504 (M+1)

Reference Example 221 1-tert-butyl3-methyl(3R,5S)-5-[{[3-(4-methoxybutyl)imidazo[1,2-a]pyridin-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate

Ethyl 3-(4-methoxybutyl)imidazol, 2-a]pyridine-2-carboxylate (183 mg)was dissolved in ethanol (5 ml), lithium hydroxide monohydrate (139 mg)was added and the mixture was stirred at 60° C. for 15 hr. The reactionmixture was concentrated under reduced pressure, and the residue wasdissolved in acetonitrile (5 ml). 1-tert-Butyl 3-methyl(3R,5S)-5-[(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (208 mg),N,N-diisopropylethylamine (570 μl) andchloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (370 mg)were added and the mixture was stirred at room temperature for 15 hr.The reaction mixture was concentrated, and the residue was diluted withaqueous sodium bicarbonate, and extracted with ethyl acetate. Theextract was washed with saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure. The residuewas subjected to basic silica gel column chromatography, and a fractioneluted with ethyl acetate was concentrated under reduced pressure togive the object product (224 mg).

MS (ESI+, m/e) 545 (M+1)

In the same manner as in Reference Example 172, the following compound(Reference Example 222) was obtained.

Reference Example 222(3R,5S)-1-(tert-butoxycarbonyl)-5-[{[3-(4-methoxybutyl)imidazo[1,2-a]pyridin-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid

MS (ESI+, m/e) 531 (M+1)

In the same manner as in Reference Example 39, the following compounds(Reference Examples 223-224) were obtained.

Reference Example 223 tert-butyl(3S,5R)-3-[{3-(4-methoxybutyl)imidazo[1,2-a]pyridin-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 600 (M+1)

Reference Example 224 tert-butyl(3S,5R)-3-[{[3-(4-methoxybutyl)imidazo[1,2-a]pyridin-2-yl]carbonyl}(2-methylpropyl)amino]-5-(pyrrolidin-1-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 584 (M+1)

In the same manner as in Example 12, the following compounds (Examples119-120) were obtained.

Example 1193-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]imidazo[1,2-a]pyridine-2-carboxamidedihydrochloride

MS (ESI+, m/e) 500 (M+1)

Example 1203-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(pyrrolidin-1-ylcarbonyl)piperidin-3-yl]imidazo[1,2-a]pyridine-2-carboxamidedihydrochloride

MS (ESI+, m/e) 484 (M+1)

Example 121N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]quinoline-2-carboxamide2 TFA salt

A 0.08M solution (1000 μL, 80 μmol) of tert-butyl(3S,5R)-3-[(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylatein DMF and quinoline-2-carboxylic acid (15.2 mg, 88 mol) were mixed, a0.32M solution (500 μL, 160 μmol) ofchloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate andN,N-diisopropylethylamine in DMF was added at room temperature and themixture was stirred for 16 hr. After completion of the reaction, 2%aqueous sodium hydrogen carbonate solution (1.0 ml) was added, andextracted with ethyl acetate (3.5 ml). The organic layer was separatedby upper layer Phase Septube (manufactured by Wako'Pure ChemicalIndustries, Ltd.). The solvent was evaporated under reduced pressure,and the residue was dissolved in DMSO-methanol (1:1) (1 ml), purified bypreparative HPLC, and the object fraction was concentrated to give aprotected title compound. 1M MSA acetonitrile solution (3 ml) was addedto the obtained protected compound, and the mixture was stirred at roomtemperature for 16 hr. After completion of the reaction, 1M DIEAacetonitrile solution (3.5 ml) was added, and the reaction mixture wasdirectly developed by preparative HPLC to give the object product (12.3mg).

MS (ESI+): 425 (M+H)

In the same manner as in Example 121, the following compounds (Examples122-124) were obtained.

Example 122N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]isoquinoline-3-carboxamide2TFA salt

MS (ESI+): 425 (M+H)

Example 1235-fluoro-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamideTFA salt

MS (ESI+): 432 (M+H)

Example 1245-chloro-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamideTFA salt

MS (ESI+): 448 (M+H)

Example 125N-{(3S,5R)-5-[(1R)-1-hydroxy-2-methoxyethyl]piperidin-3-yl}-1-(4-methoxybutyl)-N-(2-methylpropyl)-1H-benzimidazole-2-carboxamidedihydrochloride (Example 125-1) andN-{(3S,5R)-5-[(1S)-[1-hydroxy-2-methoxyethyl]piperidin-3-yl}-1-(4-methoxybutyl)-N-(2-methylpropyl)-1H-benzimidazole-2-carboxamidedihydrochloride (Example 125-2)

tert-Butyl(3R,5S)-3-(1-hydroxy-2-methoxyethyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate(7.3 g) and vinyl acetate (146 ml) were dissolved in isopropanol (292ml), lipase (Toyobo, LIP-301, 20 g) was added at room temperature, andthe mixture was stirred at room temperature for 24 hr. The completion ofthe reaction was confirmed by HPLC, and the reaction mixture wasfiltered. The filtrate was concentrated under reduced pressure, and theresidue was subjected to silica gel column chromatography, and afraction eluted with ethyl acetate-hexane (1:9-1:0) was concentratedunder reduced pressure to give a first elution component (3.76 g) and asecond elution component (3.15 g). It was confirmed that the firstelution component was a compound of Example 73-1 wherein the hydroxylgroup was acetylated, and the second elution component (99.9% de) wasthe same as the compound of Example 73-2.

The obtained first elution component (100 mg) was dissolved in methanol(1 ml), 1M aqueous sodium hydroxide solution (1 ml) was added and themixture was stirred at room temperature for 1 hr. 1M Hydrochloric acid(1 ml) was added to the reaction mixture for neutralization and methanolwas evaporated under reduced pressure. The concentrate was diluted withwater, and the mixture was extracted with ethyl acetate. The extract waswashed with saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was dissolved inethanol (1 ml), 12M hydrochloric acid (0.50 ml) was added and themixture was stirred at room temperature for 1 hr. The reaction mixturewas concentrated under reduced pressure, the residue was dissolved inethanol, and ethanol was evaporated under reduced pressure. Thisoperation was repeated twice to give the object product (52 mg) ofExample compound 125-1.

Example 125-1 Spectrum Data

¹H-NMR (CDCl₃) δ 0.71 (2H, dd), 0.95 (4H, dd), 1.38-1.63 (2H, m),1.66-1.86 (3H, m), 1.86-2.04 (1H, m), 2.12 (2H, dd), 2.59-2.91 (1H, m),3.02 (1H, d), 3.09-3.22 (4H, m), 3.24-3.39 (9H, m), 3.50 (2H, br s),3.62 (1H, br s), 4.15 (2H, br s), 4.21-4.39 (2H, m), 7.15-7.53 (2H, m),7.55-7.87 (2H, m), 8.33-9.18 (1H, m), 9.43 (1H, br s)

MS (ESI+, m/e) 461 (M+1)

The obtained second elution component (447 mg) was dissolved in ethanol(1 ml), 12M hydrochloric acid (0.70 ml) was added and the mixture wasstirred at room temperature for 1 hr. The reaction mixture wasconcentrated under reduced pressure, the residue was dissolved inethanol, and ethanol was evaporated under reduced pressure. Thisoperation was repeated twice to give the object product (365 mg) ofExample compound 125-2.

Example 125-2 Spectrum Data

¹H-NMR (CDCl₃) δ 0.71 (2H, dd), 0.81-1.12 (4H, m), 1.31-1.61 (2H, m),1.62-1.98 (5H, m), 1.98-2.23 (2H, m), 2.57-2.87 (1H, m), 3.14 (1H, d),3.18-3.23 (3H, m), 3.23-3.39 (10H, m), 3.39-3.63 (3H, m), 4.23-4.38 (3H,m), 7.16-7.51 (2H, m), 7.55-7.86 (2H, m), 8.29-9.11 (1H, m), 9.38 (1H,br s)

MS (ESI+, m/e) 461 (M+1)

Example 126N-{(3S,5R)-5-[(1S)-1-hydroxyethyl]piperidin-3-yl}-1-(4-methoxybutyl)-N-(2-methylpropyl)-1H-benzimidazole-2-carboxamidedihydrochloride (Example 126-1) andN-{(3S,5R)-5-[(1R)-1-hydroxyethyl]piperidin-3-yl}-1-(4-methoxybutyl)-N-(2-methylpropyl)-1H-benzimidazole-2-carboxamidedihydrochloride (Example 126-2)

tert-Butyl(3R,5S)-3-(1-hydroxyethyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate(39.95 g) and vinyl acetate (789 ml) were dissolved in isopropanol (1.6l), lipase (Toyobo, LIP-301, 120 g) was added at room temperature, andthe mixture was stirred at room temperature for 15 hr. The completion ofthe reaction was confirmed by HPLC, and the reaction mixture wasfiltered. The filtrate was concentrated under reduced pressure, and theresidue was subjected to silica gel column chromatography, and afraction eluted with ethyl acetate-hexane (1:9-1:0) was concentratedunder reduced pressure to give a first elution component (23.3 g) and asecond elution component (18.3 g). It was confirmed that the firstelution component was a compound of Example 74-1 wherein the hydroxylgroup was acetylated, and the second elution component (99.8% de) wasthe same as the compound of Example 74-2.

The obtained first elution component (100 mg) was dissolved in methanol(1 ml), 1M aqueous sodium hydroxide solution (1 ml) was added and themixture was stirred at room temperature for 1 hr. 1M Hydrochloric acid(1 ml) was added to the reaction mixture for neutralization and methanolwas evaporated under reduced pressure. The concentrate was diluted withwater, and the mixture was extracted with ethyl acetate. The extract waswashed with saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was dissolved inethanol (1 ml), 12M hydrochloric acid (0.50 ml) was added and themixture was stirred at room temperature for 1 hr. The reaction mixturewas concentrated under reduced pressure, the residue was dissolved inethanol, and ethanol was evaporated under reduced pressure. Thisoperation was repeated twice to give the object product (75 mg) ofExample compound 126-1.

Example 126-1 Spectrum Data

¹H-NMR (CDCl₃) δ 0.72 (3H, dd), 0.84-1.18 (7H, m), 1.45-1.66 (3H, m),1.67-1.98 (3H, m), 2.00-2.19 (2H, m), 2.54-2.81 (1H, m), 2.92-3.23 (5H,m), 3.25-3.40 (4H, m), 3.40-3.70 (3H, m), 4.07-4.47 (3H, m), 7.23-7.51(2H, m), 7.54-7.91 (2H, m), 8.56-9.55 (1H, m), 9.86 (1H, d)

MS (ESI+, m/e) 431 (M+1)

The obtained second elution component (1.0 g) was dissolved in 10%hydrogen chloride containing methanol solution (40 ml), and the mixturewas stirred at room temperature for 15 hr. The reaction mixture wasconcentrated under reduced pressure, the residue was dissolved inethanol, and ethanol was evaporated under reduced pressure. Thisoperation was repeated twice to give the object product (0.86 g) ofExample compound 126-2.

Example 126-2 Spectrum Data

¹H-NMR (CDCl₃) δ 0.71 (3H, dd), 0.94 (3H, d), 1.09 (3H, dd), 1.27-1.64(3H, m), 1.70 (1H, s), 1.74-2.00 (4H, m), 2.00-2.29 (1H, m), 2.54-2.76(1H, m), 3.11 (1H, d), 3.20 (4H, d), 3.24-3.62 (7H, m), 4.32 (3H, d),7.16-7.54 (2H, m), 7.72 (2H, q), 8.27-9.22 (1H, m), 9.36-9.56 (1H, m)

MS (ESI+, m/e) 431 (M+1)

Example 127N-{(3S,5R)-5-[(1S)-1-hydroxypropyl]piperidin-3-yl}-1-(4-methoxybutyl)-N-(2-methylpropyl)-1H-benzimidazole-2-carboxamidedihydrochloride (Example 127-1) andN-{(3S,5R)-5-[(1R)-1-hydroxypropyl]piperidin-3-yl}-1-(4-methoxybutyl)-N-(2-methylpropyl)-1H-benzimidazole-2-carboxamidedihydrochloride (Example 127-2)

tert-Butyl(3R,5S)-3-(1-hydroxypropyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate(16.4 g) and vinyl acetate (328 ml) were dissolved in isopropanol (656ml), lipase (Toyobo, LIP-301, 65.6 g) and molecular sieves 4A (65.6 g)were added at room temperature, and the mixture was stirred at roomtemperature for 77 hr. Lipase (Toyobo, LIP-301, 8.2 g) was added to thereaction mixture, and the mixture was stirred at room temperature for118 hr. Lipase (Toyobo, LIP-301, 16.4 g) was again added to the reactionmixture, and the mixture was stirred at room temperature for 140 hr.Lipase (Toyobo, LIP-301, 16.4 g) was further added to the reactionmixture, and the mixture was stirred at room temperature for 333 hr. Thecompletion of the reaction was confirmed by HPLC, and the reactionmixture was filtered. The filtrate was concentrated under reducedpressure, and the residue was subjected to silica gel columnchromatography, and a fraction eluted with ethyl acetate-hexane(1:9-3:2) was concentrated under reduced pressure to give a firstelution component (9.5 g) and a second elution component (8.0 g). It wasconfirmed that the first elution component was a compound of Example75-1 wherein the hydroxyl group was acetylated, and the second elutioncomponent (99.7% de) was the same as the compound of Example 75-2.

The obtained first elution component (100 mg) was dissolved in methanol(1 ml), 1M aqueous sodium hydroxide solution (1 ml) was added and themixture was stirred at room temperature for 1 hr. 1M Hydrochloric acid(1 ml) was added to the reaction mixture for neutralization and methanolwas evaporated under reduced pressure. The concentrate was diluted withwater, and the mixture was extracted with ethyl acetate. The extract waswashed with saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was dissolved inethanol (1 ml), 12M hydrochloric acid (0.50 ml) was added and themixture was stirred at room temperature for 1 hr. The reaction mixturewas concentrated under reduced pressure, the residue was dissolved inethanol, and ethanol was evaporated under reduced pressure. Thisoperation was repeated twice to give the object product (62 mg) ofExample compound 127-1.

Example 127-1 Spectrum Data

¹H-NMR (CDCl₃) δ 0.71 (2H, dd), 0.79-1.11 (7H, m), 1.32-1.58 (4H, m),1.60-1.68 (1H, m), 1.70-1.85 (3H, m), 1.87-2.20 (2H, m), 2.59-2.87 (1H,m), 3.00 (1H, d), 3.08-3.23 (4H, m), 3.23-3.41 (6H, m), 3.49 (1H, d),3.89-4.23 (2H, m), 4.23-4.55 (2H, m), 7.16-7.52 (2H, m), 7.55-7.86 (2H,m), 8.24-9.18 (1H, m), 9.21-9.57 (1H, m)

MS (ESI+, m/e) 445 (M+1)

The obtained second elution component (0.85 g) was dissolved in ethanol(2 ml), 12M hydrochloric acid (1.5 ml) was added, and the mixture wasstirred at room temperature for 1 hr. The reaction mixture wasconcentrated under reduced pressure, the residue was dissolved inethanol, and ethanol was evaporated under reduced pressure. Thisoperation was repeated twice to give the object product (0.64 g) ofExample compound 127-2.

Example 127-2 Spectrum Data

¹H-NMR (CDCl₃) δ 0.71 (2H, dd), 0.78-1.01 (7H, m), 1.26-1.66 (4H, m),1.66-1.86 (4H, m), 1.93 (1H, d), 2.02-2.23 (1H, m), 2.53-2.84 (1H, m),3.03-3.24 (5H, m), 3.31 (5H, q), 3.37-3.56 (2H, m), 4.16 (2H, br s),4.22-4.44 (2H, m), 7.16-7.54 (2H, m), 7.54-7.87 (2H, m), 8.16-9.27 (1H,m), 9.36-9.84 (1H, m)

MS (ESI+, m/e) 445 (M+1)

In the same manner as in Reference Example 82, the following compound(Reference Example 225) was obtained.

Reference Example 225 tert-butyl(3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-[(4-methoxypiperidin-1-yl)carbonyl]piperidine-1-carboxylate

MS (ESI+, m/e) 628 (M+1)

In the same manner as in Example 25, the following compound (Example128) was obtained.

Example 1281-(4-methoxybutyl)-N-{(3S,5R)-5-[(4-methoxypiperidin-1-yl)carbonyl]piperidin-3-yl}-N-(2-methylpropyl)-1H-benzimidazole-2-carboxamidedihydrochloride

Example 1291-(3-ethoxypropyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidetrifluoroacetate

A 0.16M solution (500 μL, 80 mol) of tert-butyl(3S,5R)-3-[(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylatein toluene, a 0.32M solution (500 μL, 160 μmol) of triphenylphosphine intoluene, and a 0.32M solution (500 μL, 160 μmol) of 3-ethoxypropan-1-olin toluene were mixed, diisopropyl azodicarboxylate (30 μL, 160 μmol)was added at room temperature and the mixture was stirred for 16 hr. 4NHydrochloric acid-ethyl acetate solution (2.0 ml) was added to thereaction mixture, and the mixture was further stirred at roomtemperature for 5 hr. 4N Aqueous sodium hydroxide solution (2.0 ml) wasadded, and the mixture was neutralized and extracted. The organic layerwas separated by upper layer Phase Septube (manufactured by Wako PureChemical Industries, Ltd.). The solvent was evaporated under reducedpressure, and the residue was dissolved in DMSO-methanol (1:1) (1 ml)and purified by preparative HPLC. The object fraction was concentrated,and the residue was diluted with aqueous calcium carbonate solution andextracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure to give the title compound (38.4 mg).

MS (ESI+): 500 (M+H)

In the same manner as in Example 129, the following compounds (Examples130-146) were obtained.

Example 1301-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidetrifluoroacetate

MS (ESI+, m/e) 500 (M+1)

Example 1311-(3-methoxypropyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidetrifluoroacetate

MS (ESI+, m/e) 486 (M+1)

Example 132N-(2-methylpropyl)-1-[3-(methylsulfanyl)propyl]-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidetrifluoroacetate

MS (ESI+, m/e) 502 (M+1)

Example 133N-(2-methylpropyl)-1-[2-(methylsulfanyl)ethyl]-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidetrifluoroacetate

MS (ESI+, m/e) 488 (M+1)

Example 1341-ethyl-N-(2-methylpropyl)-N-[(3R,5S)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidetrifluoroacetate

MS (ESI+, m/e) 442 (M+1)

Example 1351-(1-methylethyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidetrifluoroacetate

MS (ESI+, m/e) 456 (M+1)

Example 136N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1-propyl-1H-benzimidazole-2-carboxamidetrifluoroacetate

MS (ESI+, m/e) 456 (M+1)

Example 1371-butyl-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidetrifluoroacetate

MS (ESI+, m/e) 470 (M+1)

Example 138N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1-(pent-3-yn-1-yl)-1H-benzimidazole-2-carboxamidetrifluoroacetate

MS (ESI+, m/e) 480 (M+1)

Example 1391-[(2-methylcyclopropyl)methyl]-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidetrifluoroacetate

MS (ESI+, m/e) 482 (M+1)

Example 1401-(2,2-difluoroethyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidetrifluoroacetate

MS (ESI+, m/e) 478 (M+1)

Example 141N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1-(3,3,3-trifluoropropyl)-1H-benzimidazole-2-carboxamidetrifluoroacetate

MS (ESI+, m/e) 510 (M+1)

Example 142N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1-(4,4,4-trifluorobutyl)-1H-benzimidazole-2-carboxamidetrifluoroacetate

MS (ESI+, m/e) 524 (M+1)

Example 143N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1-(4-oxopentyl)-1H-benzimidazole-2-carboxamidetrifluoroacetate

MS (ESI+, m/e) 498 (M+1)

Example 144N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1-(2-(pyridin-2-yl)ethyl)-1H-benzimidazole-2-carboxamideditrifluoroacetate

MS (ESI+, m/e) 519 (M+1)

Example 145N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1-(2-(pyridin-3-yl)ethyl)-1H-benzimidazole-2-carboxamideditrifluoroacetate

MS (ESI+, m/e) 519 (M+1)

Example 146N-(2-methylpropyl)-1-[2-(4-methyl-1,3-thiazol-5-yl)ethyl]-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidetrifluoroacetate

MS (ESI+, m/e) 539 (M+1)

Reference Example 225 ethyl2-tert-butyl-6-oxo-1,6-dihydropyrimidine-5-carboxylate

To a solution of diethyl 2,2-dimethylpropanimidamide hydrochloride (1.36g) and (ethoxymethylene)malonate (2.16 g) in ethanol (100 ml) was added20% sodium ethoxide-ethanol solution (6.8 g) under ice-cooling, and themixture was stirred at 80° C. for 5 hr. The reaction mixture wasconcentrated under reduced pressure, 1M hydrochloric acid (10 ml) wasadded under ice-cooling, and the mixture was extracted with ethylacetate. The extract was concentrated under reduced pressure, hexane wasadded to the residue, and the precipitate was collected by filtration togive the object product (1.65 g) as a powder.

MS (ESI+, m/e) 225 (M+1)

¹H-NMR (CDCl₃) δ 1.33-1.41 (3H, m), 1.43 (9H, s), 4.32-4.41 (2H, m),8.72 (1H, s).

Reference Example 2262-tert-butyl-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid

Ethyl 2-tert-butyl-6-oxo-1,6-dihydropyrimidine-5-carboxylate (43.9 g)was dissolved in ethanol (200 ml), 2M aqueous sodium hydroxide solution(330 ml) was added and the mixture was stirred at room temperature for40 hr. The reaction mixture was concentrated under reduced pressure, andaqueous layer of the mixture was adjusted to pH 8 with 6M hydrochloricacid. The mixture was concentrated under reduced pressure and azeotropedwith 2-propanol. The residue was suspended in acetone, and insolublepowder was collected by filtration. The obtained powder was suspended in1M hydrochloric acid and the mixture was adjusted to pH 3, andconcentrated under reduced pressure. The residue was azeotroped with2-propanol, and the insoluble material was suspended in acetone andfiltered off. The filtrate was concentrated under reduced pressure togive the object product (32.8 g) as a powder.

¹H-NMR (DMSO-d₆) δ 1.45 (9H, s), 8.99 (1H, s), 10.59 (1H, br s), 12.47(1H, br s).

Reference Example 227 1-tert-butyl3-methyl(3R,5S)-5-{[(2-tert-butyl-4-chloropyrimidin-5-yl)carbonyl](isobutyl)amino}piperidine-1,3-dicarboxylate

2-tert-Butyl-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid (3.25 g) wasdissolved in THF (60 ml), thionyl chloride (4.3 ml) and DMF (5 drops)were added and the mixture was heated under reflux with stirring for 2.5hr. The reaction mixture was cooled to room temperature, concentratedunder reduced pressure, and the residue was azeotroped with toluene. Theobtained residue was suspended in THF (50 ml), and the suspension wasadded to a solution of 1-tert-butyl 3-methyl(3R,5S)-5-(isobutylamino)piperidine-1,3-dicarboxylate (4.13 g) anddiisopropylethylamine (9.15 μl) in THF (50 ml) and the mixture wasstirred at room temperature for 8 hr. The reaction mixture wasconcentrated under reduced pressure, diluted with water, and extractedwith ethyl acetate. The extract was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The residue was subjected to silica gel columnchromatography, and a fraction eluted with ethyl acetate-hexane(1:19-2:3) was concentrated under reduced pressure to give the objectproduct (6.29 g).

MS (ESI+, m/e) 511 (M+1)

Reference Example 228 1-tert-butyl3-methyl(3R,5S)-5-{[(2-tert-butyl-4-(hex-1-yn-1-yl)pyrimidin-5-yl)carbonyl](2-methylpropyl)amino}piperidine-1,3-dicarboxylate

1-tert-Butyl3-methyl(3R,5S)-5-{[(2-tert-butyl-4-chloropyrimidin-5-yl)carbonyl](isobutyl)amino}piperidine-1,3-dicarboxylate(300 mg), dichloro[bis(triphenylphosphine)]palladium (412 mg), copperiodide (112 mg) and N,N-diisopropylethylamine (0.51 μL) were dissolvedin DMF (8 ml), and the mixture was stirred at room temperature for 15min. 1-Hexyne (0.08 ml) was added and the mixture was stirred at roomtemperature 2 hr, and further at 70° C. for 8 hr. The mixture was cooledto room temperature, adsorbed to silica gel (10 g), and a fractioneluted with ethyl acetate was concentrated under reduced pressure. Theresidue was subjected to silica gel column chromatography, and afraction eluted with hexane-ethyl acetate (95:5-30:70) was concentratedunder reduced pressure to give the object product (218 mg).

MS (ESI+, m/e) 557 (M+1)

Reference Example 229 1-tert-butyl3-methyl(3R,5S)-5-{[(2-tert-butyl-4-hexylpyrimidin-5-yl)carbonyl](2-methylpropyl)amino}piperidine-1,3-dicarboxylate

1-tert-Butyl3-methyl(3R,5S)-5-{[(2-tert-butyl-4-(hex-1-yn-1-yl)pyrimidin-5-yl)carbonyl](2-methylpropyl)amino}piperidine-1,3-dicarboxylate(218 mg) and palladium-carbon (20 mg) were suspended in methanol and themixture was stirred under a hydrogen atmosphere (1 atom) at roomtemperature for 16 hr. The palladium catalyst was filtered off, and thefiltrate was concentrated under reduced pressure to give the objectproduct (219 mg) as a solid.

MS (ESI+, m/e) 561 (M+1)

Reference Example 230 tert-butyl(3S,5R)-3-{[(2-tert-butyl-4-hexylpyrimidin-5-yl)carbonyl](2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

1-tert-Butyl3-methyl(3R,5S)-5-{[(2-tert-butyl-4-hexylpyrimidin-5-yl)carbonyl](2-methylpropyl)amino}piperidine-1,3-dicarboxylate(219 mg) was dissolved in methanol (3 ml) and THF (2 ml), 1M aqueoussodium hydroxide solution (2 ml) was added and the mixture was stirredat room temperature for 2 hr. The reaction mixture was concentratedunder reduced pressure, and the aqueous layer of the mixture wasadjusted to pH 5-6 with saturated aqueous ammonium chloride solution,and the mixture was extracted with ethyl acetate. The extract was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure. The obtained residue,morpholine (41 μl), 1H-benzotriazol-1-ol (30 mg) and triethylamine (140μl) were dissolved in 1,2-dichloroethane (4 ml), WSC.HCl (115 mg) wasadded and the mixture was stirred at room temperature for 3 days. Thereaction mixture was poured into water, and the mixture was extractedwith ethyl acetate. The extract was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The residue was subjected to silica gel columnchromatography, and a fraction eluted with ethyl acetate-hexane(5:95-80:20) was concentrated under reduced pressure to give the objectproduct (88 mg).

MS (ESI+, m/e) 616 (M+1)

Reference Example 2314-chloro-1-(4-methoxybutyl)-2-phenyl-1H-imidazole-5-carbaldehyde

To a solution of 4-chloro-2-phenyl-1H-imidazole-5-carbaldehyde (500 mg)and 4-methoxybutyl methanesulfonate (660 mg) in N,N-dimethylacetamide(10 ml) was added cesium carbonate (2.4 g); and the mixture was stirredat 90° C. for 7 hr. After cooling to room temperature, the reactionmixture was diluted with water and extracted with ethyl acetate. Theextract was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The residue was subjected to silica gel column chromatography, and afraction eluted with ethyl acetate-hexane (5:95-3:7) was concentratedunder reduced pressure to give the object product (702 mg).

¹H-NMR (CDCl₃) δ: 1.43-1.58 (2H, m), 1.76-1.88 (2H, m), 3.27 (3H, s),3.30 (2H, t), 4.31-4.40 (2H, m), 7.52 (2H, d), 7.41-7.56 (1H, m),7.56-7.69 (2H, m), 9.85 (1H, s).

MS (ESI+, m/e) 293 (M+1)

In the same manner as in the method shown in Reference Example 231, thefollowing compound (Reference Example 232) was obtained.

Reference Example 2322-butyl-4-chloro-1-(4-methoxybutyl)-1H-imidazole-5-carbaldehyde

¹H-NMR (CDCl₃) δ: 0.96 (3H, t), 1.33-1.49 (2H, m), 1.60 (2H, d),1.68-1.85 (2H, m), 1.76 (2H, quin), 2.67 (1H, d), 2.67 (1H, s), 3.33(3H, s), 3.41 (2H, t), 4.27 (1H, s), 4.23 (1H, d), 9.72 (1H, s).

MS (ESI+, m/e) 273 (M+1)

Reference Example 2334-chloro-1-(4-methoxybutyl)-2-phenyl-1H-imidazole-5-carboxylic acid

To a solution of4-chloro-1-(4-methoxybutyl)-2-phenyl-1H-imidazole-5-carbaldehyde (790mg) in tert-butanol (15 ml) and 2-methyl-2-butene (1.5 ml) was addedaqueous solution (4 ml) of sodium chlorite (300 mg) and sodiumdihydrogen phosphate (400 mg), and the mixture was stirred at roomtemperature for 12 hr. 1M Hydrochloric acid was added, and the mixturewas adjusted to pH 3, and extracted with ethyl acetate. The extract waswashed with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure to give the objectproduct (730 mg).

MS (ESI+, m/e) 309 (M+1)

In the same manner as in the method shown in Reference Example 233, thefollowing compound (Reference Example 234) was obtained.

Reference Example 2342-butyl-4-chloro-1-(4-methoxybutyl)-1H-imidazole-5-carboxylic acid

MS (ESI+, m/e) 289 (M+1)

Reference Example 235 tert-butyl(3S,5R)-3-[{[4-chloro-1-(4-methoxybutyl)-2-phenyl-1H-imidazol-5-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

4-Chloro-1-(4-methoxybutyl)-2-phenyl-1H-imidazole-5-carboxylic acid (309mg), tert-butyl(3S,5R)-3-[(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(370 mg) obtained in Reference Example 22 and N,N-diisopropylethylamine(270 μl) were dissolved in 1,2-dichloroethane (8 ml),chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (340 mg)was added and the mixture was stirred at room temperature for 4 days.The reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract waswashed with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wassubjected to silica gel column chromatography, and a fraction elutedwith ethyl acetate-hexane (10:90-100:0) was concentrated under reducedpressure to give the object product (425 mg).

MS (ESI+, m/e) 661 (M+1)

In the same manner as in the method shown in Reference Example 235, thefollowing compound (Reference Example 236) was obtained.

Reference Example 236

tert-butyl(3S,5R)-3-[{[2-butyl-4-chloro-1-(4-methoxybutyl)-1H-imidazol-5-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 641 (M+1)

Reference Example 237 tert-butyl(3S,5R)-3-[{[1-(4-methoxybutyl)-2-phenyl-1H-imidazol-5-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

tert-Butyl(3S,5R)-3-[{[4-chloro-1-(4-methoxybutyl)-2-phenyl-1H-imidazol-5-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(200 mg), palladium(II) hydroxide-carbon (20 mg) and potassium acetate(30 mg) were suspended in methanol (10 ml), and the mixture was stirredunder a hydrogen atmosphere (1 atom) at room temperature for 1 day. Thepalladium catalyst was filtered off and the filtrate was concentratedunder reduced pressure. The residue was suspended in water, and thesuspension was extracted with ethyl acetate. The extract was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The residue was subjected tosilica gel column chromatography, and a fraction eluted with ethylacetate-hexane (10:90-80:20) was concentrated under reduced pressure togive the object product (90 mg).

MS (ESI+, m/e) 626 (M+1)

In the same manner as in the method shown in Reference Example 237, thefollowing compound (Reference Example 238) was obtained.

Reference Example 238 tert-butyl(3S,5R)-3-[{[2-butyl-1-(4-methoxybutyl)-1H-imidazol-5-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 606 (M+1)

Reference Example 239 tert-butyl N-[cyclohexyl(imino)methyl]glycinate

To a solution of cyclohexanecarboximidamide hydrochloride (2.00 g) andtert-butyl glycinate hydrochloride (2.06 g) in DMF (16 ml) was addedtriethylamine (4.30 ml) at room temperature, and the mixture was stirredat 60° C. for 3 hr. The reaction mixture was cooled to room temperature,diluted with water, and the mixture was extracted with ethyl acetate.The extract was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure togive the object product (0.84 g).

¹H-NMR (CDCl₃) δ: 1.26-1.34 (4H, m), 1.48 (7H, d), 1.63-1.78 (2H, m),1.79-1.91 (1H, m), 1.84 (2H, dd), 1.97 (2H, d), 2.43 (1H, t), 3.93-4.02(1H, m), 4.09 (2H, d).

Reference Example 240 4-chloro-2-cyclohexyl-1H-imidazole-5-carbaldehyde

tert-Butyl N-[cyclohexyl(imino)methyl]glycinate (830 mg) was dissolvedin a solution (10%, 15 ml) of trifluoroacetic acid in 1,2-dichloroethaneand the mixture was stirred at room temperature for 1 day. The reactionmixture was concentrated under reduced pressure. The residue wassuspended in toluene, phosphorus oxychloride (3.21 ml) was added and themixture was stirred at 80° C. for 30 min. DMF (2.67 ml) was added andthe mixture was stirred at 100° C. for 5 hr. The reaction mixture wasice-cooled, basified by pouring into an aqueous sodium hydroxidesolution, and extracted with ethyl acetate. The extract was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The residue was subjected tosilica gel column chromatography, and a fraction eluted with ethylacetate-hexane (10:90-100:0) was concentrated under reduced pressure togive the object product (495 mg).

¹H-NMR (CDCl₃) δ: 1.22-1.34 (1H, m), 1.39 (1H, dt), 1.57 (2H, qd), 1.74(1H, ddd), 1.80-1.89 (1H, m), 1.83 (2H, dd), 2.02 (1H, d), 2.06 (1H, d),2.79 (1H, tt), 9.65 (1H, s), 10.59 (1H, br s).

In the same manner as in the method shown in Reference Example 231, thefollowing compound (Reference Example 241) was obtained.

Reference Example 2414-chloro-2-cyclohexyl-1-(4-methoxybutyl)-1H-imidazole-5-carbaldehyde

¹H-NMR (CDCl₃) δ: 1.27-1.43 (3H, m), 1.60-1.67 (3H, m), 1.69-1.81 (6H,m), 1.84-1.89 (2H, m), 2.65 (1H, tt), 3.29-3.46 (6H, m), 4.25 (2H, t),9.71 (1H, s).

In the same manner as in the method shown in Reference Example 233, thefollowing compound (Reference Example 242) was obtained.

Reference Example 2424-chloro-2-cyclohexyl-1-(4-methoxybutyl)-1H-imidazole-5-carboxylic acid

MS (ESI+, m/e) 315 (M+1)

In the same manner as in the method shown in Reference Example 235, thefollowing compound (Reference Example 243) was obtained.

Reference Example 243 tert-butyl(3S,5R)-3-[{[4-chloro-2-cyclohexyl-1-(4-methoxybutyl)-1H-imidazol-5-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 667 (M+1)

In the same manner as in the method shown in Reference Example 237, thefollowing compound (Reference Example 244) was obtained.

Reference Example 244 tert-butyl(3S,5R)-3-[{[2-cyclohexyl-1-(4-methoxybutyl)-1H-imidazol-5-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 632 (M+1)

Reference Example 245 methyl 2-diazo-7-methoxy-3-oxoheptanoate

To a solution (100 ml) of methyl 7-methoxy-3-oxoheptanoate (5.00 g) and4-(acetylamino)benzenesulfonyl azide (7.02 g) in acetonitrile was addedtriethylamine (11.1 ml) and the mixture was stirred at room temperaturefor 2 days. Insoluble material was filtered through celite, and thefiltrate was concentrated under reduced pressure. The residue wassuspended in diethyl ether and the insoluble material was filtered off.The filtrate was concentrated under reduced pressure to give the objectproduct (6.93 g).

¹H-NMR (CDCl₃) δ: 1.49-1.83 (4H, m), 2.88 (2H, t), 3.32 (3H, s), 3.39(2H, t), 3.84 (3H, s).

Reference Example 246 methyl5-(4-methoxybutyl)-2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-carboxylate

Methyl 2-diazo-7-methoxy-3-oxoheptanoate (6.93 g) and 1-phenylurea (5.41g) were suspended in toluene (30 ml)-1,2-dichloroethane (30 ml), rhodiumtetraacetate (230 mg) was added and the mixture was stirred at 80° C.for 2 hr. After cooling to room temperature, trifluoroacetic acid (7.5ml) was added and the reaction mixture was stirred at room temperaturefor 1 day. The reaction mixture was concentrated under reduced pressure,and the residue was subjected to silica gel column chromatography, and afraction eluted with ethyl acetate-hexane (15:85-100:0) was concentratedunder reduced pressure to give the object product (7.40 g).

MS (ESI+, m/e) 305 (M+1)

Reference Example 247 methyl2-chloro-5-(4-methoxybutyl)-1-phenyl-1H-imidazole-4-carboxylate

Methyl5-(4-methoxybutyl)-2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-carboxylate(1.50 g) was dissolved in phosphorus oxychloride (18 ml) and the mixturewas stirred at 100° C. for 10 hr. After cooling to room temperature, thereaction mixture was concentrated under reduced pressure. The residuewas diluted with saturated aqueous sodium hydrogen carbonate solutionand the mixture was extracted with ethyl acetate. The extract was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure. The residue was subjectedto silica gel column chromatography, and a fraction eluted with ethylacetate-hexane (10:90-100:0) was concentrated under reduced pressure togive the object product (454 mg).

¹H-NMR (CDCl₃) δ: 1.37-1.53 (4H, m), 2.72-2.88 (2H, m), 3.16-3.33 (5H,m), 3.92 (3H, s), 7.17-7.33 (2H, m), 7.51-7.57 (3H, m).

Reference Example 2482-chloro-5-(4-methoxybutyl)-1-phenyl-1H-imidazole-4-carboxylic acid

Methyl 2-chloro-5-(4-methoxybutyl)-1-phenyl-1H-imidazole-4-carboxylate(450 mg) was dissolved in methanol (5 ml), 1M aqueous sodium hydroxidesolution (4.2 ml) was added and the mixture was stirred at 80° C. for 2hr. After cooling to room temperature, the reaction mixture wasconcentrated under reduced pressure. The residue was acidified with 1Mhydrochloric acid and extracted with ethyl acetate. The extract waswashed with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure to give the objectproduct (372 mg).

MS (ESI+, m/e) 309 (M+1)

In the same manner as in the method shown in Reference Example 235, thefollowing compound (Reference Example 249) was obtained.

Reference Example 249 tert-butyl(3S,5R)-3-[{[2-chloro-5-(4-methoxybutyl)-1-phenyl-1H-imidazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 661 (M+1)

In the same manner as in the method shown in Reference Example 237, thefollowing compound (Reference Example 250) was obtained.

Reference Example 250 tert-butyl(3S,5R)-3-[{[5-(4-methoxybutyl)-1-phenyl-1H-imidazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 626 (M+1)

In the same manner as in the method shown in Reference Example 231, thefollowing compound (Reference Example 251) was obtained.

Reference Example 251 ethyl1-(4-methoxybutyl)-1H-imidazole-2-carboxylate

¹H-NMR (CDCl₃) δ: 1.43 (3H, t), 1.59 (2H, dd), 1.89 (2H, quin), 3.32(3H, s), 3.39 (2H, t), 4.34-4.50 (4H, m), 7.12 (2H, d).

MS (ESI+, m/e) 227 (M+1)

Reference Example 252 ethyl4-bromo-1-(4-methoxybutyl)-1H-imidazole-2-carboxylate

Ethyl 1-(4-methoxybutyl)-1H-imidazole-2-carboxylate (2.18 g) wasdissolved in acetonitrile (30 ml), N-bromosuccinimide (1.71 g) was addedand the mixture was stirred at 60° C. for 14 hr. After cooling to roomtemperature, the reaction mixture was concentrated under reducedpressure. The residue was subjected to silica gel column chromatography,and a fraction eluted with ethyl acetate-hexane (10:90-70:30) wasconcentrated under reduced pressure to give the object product (689 mg).

¹H-NMR (CDCl₃) δ: 1.42 (3H, t), 1.60 (2H, dd), 1.89 (2H, quin), 3.33(3H, s), 3.40 (2H, t), 4.34-4.50 (4H, m), 7.08 (1H, s).

MS (ESI+, m/e) 306 (M+1)

Reference Example 253 tert-butyl(3S,5R)-3-[{[4-bromo-1-(4-methoxybutyl)-1H-imidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

Ethyl 4-bromo-1-(4-methoxybutyl)-1H-imidazole-2-carboxylate (290 mg) andlithium hydroxide monohydrate (60 mg) were suspended in THF (2 ml),ethanol (2 ml) and water (1 ml) and the mixture was stirred at roomtemperature for 2 hr. The reaction mixture was concentrated underreduced pressure. The obtained residue and tert-butyl(3S,5R)-3-[(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(355 mg) obtained in Reference Example 22 were suspended in1,2-dichloroethane (3 ml), chloro-N,N,N′,N′-tetramethylformamidiniumhexafluorophosphate (405 mg) was added and the mixture was stirred atroom temperature for 3 days. The reaction mixture was diluted withsaturated aqueous sodium hydrogen carbonate solution and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The residue was subjected to silicagel column chromatography, and a fraction eluted with ethylacetate-hexane (10:90-100:0) was concentrated under reduced pressure.The obtained residue was purified by reversed-phase preparative HPLC,and the object fraction was concentrated under reduced pressure. Theresidue was basified with 3.5M aqueous potassium carbonate solution, andthe mixture was extracted with ethyl acetate. The extract was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure to give the object product(117 mg).

MS (ESI+, m/e) 629 (M+1)

Reference Example 254 methyl2-methoxy-5-(4-methoxybutyl)-1-phenyl-1H-imidazole-4-carboxylate

Methyl5-(4-methoxybutyl)-2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-carboxylate(2.00 g) was dissolved in dichloromethane (14 ml), trimethyloxoniumtetrafluoroborate (2.00 g) was added and the mixture was stirred at roomtemperature for 16 hr. Saturated aqueous sodium hydrogen carbonatesolution was added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The residue was subjected to silicagel column chromatography, and a fraction eluted with ethylacetate-hexane (10:90-100:0) was concentrated under reduced pressure togive the object product (585 mg).

¹H-NMR (CDCl₃) δ: 1.35-1.51 (4H, m), 2.72-2.81 (2H, m), 3.14-3.30 (5H,m), 3.90 (3H, s), 4.02 (3H, s), 7.20-7.33 (3H, m), 7.42-7.55 (2H, m).

MS (ESI+, m/e) 319 (M+1)

Reference Example 255 methyl2-ethoxy-5-(4-methoxybutyl)-1-phenyl-1H-imidazole-4-carboxylate

Methyl5-(4-methoxybutyl)-2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-carboxylate(740 mg) was dissolved in acetonitrile (8 ml), a 1M solution (6.1 ml) oftrimethyloxonium tetrafluoroborate in dichloromethane was added and thereaction mixture was stirred at room temperature for 3 days. Saturatedaqueous sodium hydrogen carbonate solution was added to the reactionmixture, and the mixture was extracted with ethyl acetate. The extractwas washed with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure. The residuewas subjected to silica gel column chromatography, and a fraction elutedwith ethyl acetate-hexane (10:90-80:20) was concentrated under reducedpressure to give the object product (79 mg).

MS (ESI+, m/e) 333 (M+1)

In the same manner as in the method shown in Reference Example 248, thefollowing compounds (Reference Examples 256-257) were obtained.

Reference Example 2562-methoxy-5-(4-methoxybutyl)-1-phenyl-1H-imidazole-4-carboxylic acid

MS (ESI+, m/e) 305 (M+1)

Reference Example 2572-ethoxy-5-(4-methoxybutyl)-1-phenyl-1H-imidazole-4-carboxylic acid

MS (ESI+, m/e) 319 (M+1)

In the same manner as in the method shown in Reference Example 235, thefollowing compounds (Reference Examples 258-259) were obtained.

Reference Example 258 tert-butyl(3S,5R)-3-[{[2-methoxy-5-(4-methoxybutyl)-1-phenyl-1H-imidazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 656 (M+1)

Reference Example 259 tert-butyl(3S,5R)-3-[{[2-ethoxy-5-(4-methoxybutyl)-1-phenyl-1H-imidazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 670 (M+1)

Reference Example 260 methyl 2-(hydroxyimino)-7-methoxy-3-oxoheptanoate

To an aqueous solution (20 ml) of sodium nitrite (2.20 g) was addeddropwise a solution of methyl 7-methoxy-3-oxoheptanoate (5.00 g)obtained in Reference Example 359 in acetic acid (5 ml) underice-cooling, and the reaction mixture was stirred at room temperaturefor 3 hr. The reaction mixture was diluted with water, and the mixturewas extracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure to give the object product (5.91 g).

¹H-NMR (CDCl₃) δ: 1.60-1.79 (4H, m), 2.82 (2H, t), 3.38 (3H, s), 3.46(2H, t), 3.90 (3H, s).

Reference Example 261 methyl 2-(acetylamino)-7-methoxy-3-oxoheptanoate

Methyl 2-(hydroxyimino)-7-methoxy-3-oxoheptanoate (5.70 g) andpalladium-carbon (900 mg) were suspended in acetic acid (60 ml)-aceticanhydride (25 ml) and the mixture was stirred under a hydrogenatmosphere (1 atom) at room temperature for 14 hr. The palladiumcatalyst was filtered off, and the filtrate was concentrated underreduced pressure to give the object product (5.48 g).

¹H-NMR (CDCl₃) δ: 1.54-1.62 (2H, m), 1.65-1.75 (2H, m), 2.07 (3H, s),2.75 (2H, q), 3.26-3.43 (5H, m), 3.81 (3H, s), 5.26 (1H, d), 6.65 (1H,br s).

Reference Example 262 methyl5-(4-methoxybutyl)-2-methyl-1-phenyl-1H-imidazole-4-carboxylate

Methyl 2-(acetylamino)-7-methoxy-3-oxoheptanoate (5.45 g), aniline (3.01ml) and trifluoroacetic acid (2.48 ml) were dissolved in butyronitrile(30 ml), and the reaction mixture was heated under reflux for 2 hr. Thereaction mixture was cooled to room temperature and concentrated underreduced pressure. 3.6M Aqueous potassium carbonate solution was added tothe obtained residue and the mixture was extracted with ethyl acetate.The extract was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The residue was subjected to silica gel column chromatography, and afraction eluted with ethyl acetate-hexane (10:90-100:0) was concentratedunder reduced pressure to give the object product (3.88 g).

¹H-NMR (CDCl₃) δ: 1.36-1.53 (4H, m), 1.71 (2H, td), 2.21 (3H, s), 2.76(2H, t), 3.13-3.30 (3H, m), 3.91 (3H, s), 7.16-7.25 (2H, m), 7.47-7.61(3H, m).

MS (ESI+, m/e) 303 (M+1)

Reference Example 2635-(4-methoxybutyl)-2-methyl-1-phenyl-1H-imidazole-4-carboxylic acid

Methyl 5-(4-methoxybutyl)-2-methyl-1-phenyl-1H-imidazole-4-carboxylate(3.85 g) was dissolved in methanol (26 ml)-water (24 ml), lithiumhydroxide monohydrate (800 mg) was added and the mixture was heatedunder reflux for 2 hr. After cooling to room temperature, the reactionmixture was concentrated under reduced pressure. The residue wasadjusted to pH=7 with 1M hydrochloric acid, subjected to DIAION HP-20(manufactured by Mitsubishi Chemical), washed with water and a fractioneluted with acetone was concentrated under reduced pressure to give theobject product (1.08 g).

¹H-NMR (DMSO-d₆) δ: 1.28 (5H, br s), 2.07 (3H, s), 2.50 (1H, br s), 2.69(2H, br s), 3.08 (3H, s), 7.41 (2H, d), 7.51-7.67 (3H, m).

MS (ESI+, m/e) 289 (M+1)

In the same manner as in the method shown in Reference Example 235, thefollowing compound (Reference Example 264) was obtained.

Reference Example 264 tert-butyl(3S,5R)-3-[{[5-(4-methoxybutyl)-2-methyl-1-phenyl-1H-imidazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

¹H-NMR (CDCl₃) δ: 0.94 (6H, br s), 1.35-1.52 (4H, m), 1.45 (9H, d), 1.83(3H, br s), 2.02-2.19 (4H, m), 2.62 (2H, d), 2.72-2.85 (3H, m),3.11-3.27 (6H, m), 3.49 (2H, br s), 3.58-3.75 (2H, m), 3.69 (5H, dd),4.06-4.21 (2H, m), 7.17-7.33 (2H, m), 7.45-7.62 (3H, m).

MS (ESI+, m/e) 640 (M+1)

Reference Example 2655-[(benzyloxy)methyl]-1-phenyl-1H-1,2,3-triazole-4-carboxylic acid

Methyl 4-(benzyloxy)-3-oxobutanoate (5.00 g) and azidobenzene (2.68 g)were dissolved in methanol (30 ml), sodium methanolate (28% methanolsolution, 6.5 g) was added and the mixture was stirred at roomtemperature for 2 hr, and then heated under reflux for 18 hr. 1M Aqueoussodium hydroxide solution (10 ml) was added and the mixture was heatedunder reflux for 2 hr. The reaction mixture was cooled to roomtemperature and concentrated under reduced pressure. The residue wasdissolved in water and washed with ethyl acetate-hexane (1:1, v/v). Theobtained aqueous solution was acidified with 1M hydrochloric acid, andthe mixture was extracted with ethyl acetate. The extract was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure to give the object product(6.03 g).

¹H-NMR (CDCl₃) δ: 4.62 (2H, s), 4.88 (2H, s), 7.22-7.39 (5H, m),7.47-7.62 (3H, m), 7.68 (2H, dd).

MS (ESI+, m/e) 310 (M+1)

Reference Example 266 1-tert-butyl3-methyl(3R,5S)-5-[({5-[(benzyloxy)methyl]-1-phenyl-1H-1,2,3-triazol-4-yl}carbonyl)(2-methylpropyl)amino]piperidine-1,3-dicarboxylate

5-[(Benzyloxy)methyl]-1-phenyl-1H-1,2,3-triazole-4-carboxylic acid (6.00g) was dissolved in THF (50 ml), thionyl chloride (2.15 ml) and DMF (5drops) were added and the mixture was heated under reflux with stirringfor 2 hr. The reaction mixture was cooled to room temperature,concentrated under reduced pressure, and the residue was azeotroped withtoluene. The obtained residue was suspended in THF (20 ml), and thesuspension was added to a solution of 1-tert-butyl3-methyl(3R,5S)-5-(isobutylamino)piperidine-1,3-dicarboxylate (6.10 g)and diisopropylethylamine (10.0 μl) in THF (30 ml) and the mixture wasstirred at room temperature for 14 hr. The reaction mixture wasconcentrated under reduced pressure, diluted with water, and extractedwith ethyl acetate. The extract was washed successively with 1Mhydrochloric acid and saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The residue was subjected to silica gel column chromatography, and afraction eluted with ethyl acetate-hexane (5:95-70:30) was concentratedunder reduced pressure to give the object product (7.70 g).

¹H-NMR (CDCl₃) δ: 0.77-1.06 (6H, m), 1.36-1.53 (9H, m), 1.57 (2H, br s),1.80-2.00 (1H, m), 2.14-2.33 (1H, m), 2.63 (2H, br s), 2.82 (1H, br s),3.30 (1H, d), 3.56 (1H, br s), 3.71 (3H, s), 4.21-4.37 (2H, m), 4.54(2H, s), 4.76 (2H, d), 7.17-7.22 (2H, m), 7.24-7.36 (3H, m), 7.46-7.57(3H, m), 7.59-7.68 (2H, m).

MS (ESI+, m/e) 606 (M+1)

Reference Example 267 1-tert-butyl3-methyl(3R,5S)-5-[{[5-(hydroxymethyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate

1-tert-Butyl3-methyl(3R,5S)-5-[({5-[(benzyloxy)methyl]-1-phenyl-1H-1,2,3-triazol-4-yl}carbonyl)(2-methylpropyl)amino]piperidine-1,3-dicarboxylate(2.92 g) and palladium(II) hydroxide-carbon (500 mg) were suspended inmethanol, and the mixture was stirred under a hydrogen atmosphere (5atom) at room temperature for 10 hr. The palladium catalyst was filteredoff, and the filtrate was concentrated under reduced pressure to givethe object product (2.39 g) as a solid.

¹H-NMR (CDCl₃) δ: 0.96 (6H, dd), 1.46 (9H, d), 1.60-1.95 (1H, m), 2.19(1H, dt), 2.60 (1H, d), 2.68-2.93 (2H, m), 3.28 (1H, br s), 3.54 (1H, brs), 3.72 (3H, s), 4.32 (2H, br s), 4.65 (2H, d), 4.82-4.98 (2H, m), 7.57(5H, s).

MS (ESI+, m/e) 516 (M+1)

Reference Example 268(3R,5S)-(tert-butoxycarbonyl)-5-[{[5-(hydroxymethyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid

1-tert-Butyl3-methyl(3R,5S)-5-[{[5-(hydroxymethyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate(2.25 g) was dissolved in THF (10 ml)-methanol (10 ml)-water (8 ml), 8Maqueous sodium hydroxide solution (1.5 ml) was added and the reactionmixture was stirred at room temperature for 3 hr. The reaction mixturewas neutralized with saturated aqueous ammonium chloride solution,acidified with 1M hydrochloric acid and extracted with ethyl acetate.The extract was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure togive the object product (2.18 g).

MS (ESI+, m/e) 502 (M+1)

Reference Example 269 tert-butyl(3S,5R)-3-[{[5-(hydroxymethyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

(3R,5S)-1-(tert-Butoxycarbonyl)-5-[{[5-(hydroxymethyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid (2.18 g), morpholine (0.46 ml), 1H-benzotriazol-1-ol (330 mg) andtriethylamine (1.5 ml) were dissolved in acetonitrile (20 ml), WSC.HCl(1.25 g) was added and the mixture was stirred at room temperature for 3days. The reaction mixture was poured into water, and the mixture wasextracted with ethyl acetate. The extract was washed successively withsaturated aqueous sodium hydrogen carbonate solution and saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The residue was subjected to silicagel column chromatography, and a fraction eluted with ethylacetate-hexane (10:90-100:0) was concentrated under reduced pressure togive the object product (2.35 g).

¹H-NMR (CDCl₃) δ: 0.92 (2H, d), 0.98 (4H, dd), 1.42 (6H, s), 1.49 (3H,s), 2.04 (2H, s), 2.56 (1H, br s), 2.87 (3H, br s), 3.26 (1H, dd), 3.45(2H, dd), 3.60-3.76 (2H, m), 3.68 (4H, t), 4.14-4.38 (2H, m), 4.52-4.80(2H, m), 4.65 (1H, d), 4.90 (1H, dd), 7.49-7.65 (5H, m).

MS (ESI+, m/e) 571 (M+1)

Reference Example 270 tert-butyl(3S,5R)-3-[({5-[(2-methoxyethoxy)methyl]-1-phenyl-1H-1,2,3-triazol-4-yl}carbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

tert-Butyl(3S,5R)-3-[{[5-(hydroxymethyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(215 mg) was dissolved in DMF (3 ml), sodium hydride (50% in oil, 30 mg)was added under ice-cooling. The reaction mixture was stirred at roomtemperature for 30 min, 1-bromo-2-methoxyethane (55 μl) was added underice-cooling, and the mixture was further stirred at room temperature for14 hr. The reaction mixture was diluted with saturated aqueous sodiumhydrogen carbonate solution, and extracted with ethyl acetate. Theextract was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The residue was subjected to silica gel column chromatography, and afraction eluted with ethyl acetate-hexane (10:90-100:0) was concentratedunder reduced pressure to give the object product (149 mg).

MS (ESI+, m/e) 629 (M+1)

Reference Example 271 tert-butyl(3S,5R)-3-[(2-methylpropyl){[5-(phenoxymethyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

tert-Butyl(3S,5R)-3-[{[5-(hydroxymethyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(205 mg), phenol (70 mg) and triphenylphosphine (190 mg) were dissolvedin toluene (5 ml), diisopropyl azodicarboxylate (40% toluene solution,365 mg) was added, and the mixture was stirred at room temperature for12 hr. The reaction mixture was poured into saturated brine, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The residue was subjected tosilica gel column chromatography, and a fraction eluted to with ethylacetate-hexane (10:90-100:0) was concentrated under reduced pressure togive the object product (344 mg).

MS (ESI+, m/e) 647 (M+1)

In the same manner as in the method shown in Reference Example 271, thefollowing compounds (Reference Examples 272-273) were obtained.

Reference Example 272 tert-butyl(3S,5R)-3-[({5-[(3-methoxyphenoxy)methyl]-1-phenyl-1H-1,2,3-triazol-4-yl}carbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 677 (M+1)

Reference Example 273 tert-butyl(3S,5R)-3-[({5-[(4-methoxyphenoxy)methyl]-1-phenyl-1H-1,2,3-triazol-4-yl}carbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 677 (M+1)

Example 1472-tert-butyl-4-hexyl-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]pyrimidine-5-carboxamidedihydrochloride

tert-Butyl(3S,5R)-3-{[(2-tert-butyl-4-hexylpyrimidin-5-yl)carbonyl](2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(88.4 mg) was dissolved in 1M hydrogen chloride-ethyl acetate (3 ml),and the mixture was stirred at room temperature for 1.5 hr. The reactionmixture was concentrated to give the object product (62.7 mg).

MS (ESI+, m/e) 516 (M+1)

In the same manner as in the method shown in the above-mentioned Example147, the compounds described in the following Examples 148-159 wereobtained.

Example 1484-chloro-1-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-2-phenyl-1H-imidazole-5-carboxamidedihydrochloride

MS (ESI+, m/e) 561 (M+1)

Example 1491-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-2-phenyl-1H-imidazole-5-carboxamidedihydrochloride

MS (ESI+, m/e) 526 (M+1)

Example 1502-butyl-4-chloro-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-imidazole-5-carboxamidedihydrochloride

MS (ESI+, m/e) 541 (M+1)

Example 1512-butyl-1-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-imidazole-5-carboxamidedihydrochloride

MS (ESI+, m/e) 506 (M+1)

Example 1524-chloro-2-cyclohexyl-1-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-imidazole-5-carboxamidedihydrochloride

Example 1532-cyclohexyl-1-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-imidazole-5-carboxamidedihydrochloride

MS (ESI+, m/e) 532 (M+1)

Example 1544-bromo-1-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-imidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 529 (M+1)

Example 1552-chloro-5-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1-phenyl-1H-imidazole-4-carboxamidedihydrochloride

MS (ESI+, m/e) 561 (M+1)

Example 1565-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1-phenyl-1H-imidazole-4-carboxamidedihydrochloride

MS (ESI+, m/e) 526 (M+1)

Example 157N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-5-(phenoxymethyl)-1-phenyl-1H-1,2,3-triazole-4-carboxamidehydrochloride

MS (ESI+, m/e) 547 (M+1)

Example 1585-[(2-methoxyethoxy)methyl]-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1-phenyl-1H-1,2,3-triazole-4-carboxamidehydrochloride

MS (ESI+, m/e) 529 (M+1)

Example 1595-[(3-methoxyphenoxy)methyl]-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1-phenyl-1H-1,2,3-triazole-4-carboxamidehydrochloride

MS (ESI+, m/e) 577 (M+1)

Example 1605-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-carboxamidehydrochloride

tert-Butyl(3S,5R)-3-[{[2-methoxy-5-(4-methoxybutyl)-1-phenyl-1H-imidazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(94 mg) was dissolved in methanol (4 ml)-water (2 ml)-6M hydrochloricacid (2 ml), and the mixture was stirred at room temperature for 2 hrand then heated under reflux for 6 hr. The reaction mixture wasconcentrated under reduced pressure, and the residue was basified with8M aqueous sodium hydroxide solution under ice-cooling and extractedwith ethyl acetate. The extract was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The residue was dissolved in 1M hydrogenchloride-ethyl acetate (3 ml), and the mixture was stirred at roomtemperature for 10 min. The reaction mixture was concentrated to givethe object product (28 mg).

MS (ESI+, m/e) 542 (M+1)

Example 1612-methoxy-5-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1-phenyl-TH-imidazole-4-carboxamidefumarate

tert-Butyl(3S,5R)-3-[{[2-methoxy-5-(4-methoxybutyl)-1-phenyl-1H-imidazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(110 mg) was dissolved in trifluoroacetic acid (25% toluene solution, 4ml), and the mixture was stirred at room temperature for 4 hr. Thereaction mixture was basified with saturated aqueous potassium carbonatesolution, and extracted with ethyl acetate. The extract was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The residue was subjected tosilica gel column chromatography, and a fraction eluted with ethylacetate-hexane-methanol (50:50:0-100:0:0-85:0:15) was concentrated underreduced pressure. The residue was dissolved in methanol (2 ml), fumaricacid (15 mg) was added and the mixture was stirred at room temperaturefor 1 hr. The reaction mixture was concentrated under reduced pressureto give the object product (86 mg).

MS (ESI+, m/e) 556 (M+1)

In the same manner as in the method shown in the above-mentioned Example161, the compounds described in the following Examples 162-163 wereobtained.

Example 1625-(4-methoxybutyl)-2-methyl-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1-phenyl-1H-imidazole-4-carboxamidefumarate

MS (ESI+, m/e) 540 (M+1)

Example 1632-ethoxy-5-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1-phenyl-1H-imidazole-4-carboxamidefumarate

MS (ESI+, m/e) 570 (M+1)

In the same manner as in the method shown in Reference Example 265, thefollowing compounds (Reference Examples 274-275) were obtained.

Reference Example 2745-[(benzyloxy)methyl]-1-(2-fluorophenyl)-1H-1,2,3-triazole-4-carboxylicacid

¹H-NMR (CDCl₃) δ: 4.45 (2H, s), 4.65-4.78 (2H, m), 7.06 (1H, dd),7.25-7.39 (8H, m).

MS (ESI+, m/e) 328 (M+1)

Reference Example 2755-[(benzyloxy)methyl]-(2-methylphenyl)-1H-1,2,3-triazole-4-carboxylicacid

¹H-NMR (CDCl₃) δ: 2.05 (3H, s), 4.45 (2H, s), 4.65-4.78 (2H, m), 7.06(1H, dd), 7.25-7.39 (8H, m).

MS (ESI+, m/e) 324 (M+1)

In the same manner as in the method shown in Reference Example 266, thefollowing compounds (Reference Examples 276-277) were obtained.

Reference Example 276 1-tert-butyl3-methyl(3R,5S)-5-[({5-[(benzyloxy)methyl]-1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl}carbonyl)(2-methylpropyl)amino]piperidine-1,3-dicarboxylate

¹H-NMR (CDCl₃) δ: 0.89 (3H, d), 0.97 (3H, d), 1.45 (6H, d), 1.46 (3H,s), 1.93-2.06 (3H, m), 2.16-2.32 (1H, m), 2.44-2.93 (3H, m), 3.29 (1H,br s), 3.40-3.94 (2H, m), 3.70 (3H, s), 4.29-4.46 (3H, m), 4.82 (2H, d),6.99 (2H, dd), 7.20-7.36 (5H, m), 7.43-7.59 (2H, m).

MS (ESI+, m/e) 624 (M+1)

Reference Example 277 1-tert-butyl3-methyl(3R,5S)-5-[({5-[(benzyloxy)methyl]-1-(2-methylphenyl)-1H-1,2,3-triazol-4-yl}carbonyl)(2-methylpropyl)amino]piperidine-1,3-dicarboxylate

¹H-NMR (CDCl₃) δ: 0.88 (4H, t), 0.98 (2H, d), 1.44 (5H, d), 1.48 (4H,s), 1.94-2.07 (4H, m), 2.16-2.32 (1H, m), 2.46-2.62 (1H, m), 2.62-2.78(2H, m), 2.83 (1H, br s), 3.29 (1H, d), 3.49-3.64 (2H, m), 3.70 (3H, s),4.25 (1H, br s), 4.32-4.48 (3H, m), 4.57-4.73 (2H, m), 6.96-7.10 (1H,m), 7.03 (1H, d), 7.21-7.33 (6H, m), 7.43-7.50 (1H, m).

MS (ESI+, m/e) 620 (M+1)

In the same manner as in the method shown in Reference Example 267, thefollowing compounds (Reference Examples 278-279) were obtained.

Reference Example 278 1-tert-butyl3-methyl(3R,5S)-5-[{[1-(2-fluorophenyl)-5-(hydroxymethyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate

¹H-NMR (CDCl₃) δ: 0.96 (6H, dd), 1.35-1.52 (9H, m), 1.67 (1H, d),2.00-2.10 (1H, m), 2.60 (1H, d), 2.75 (2H, br s), 3.28 (1H, br s), 3.57(1H, br s), 3.61-3.77 (3H, m), 4.06-4.65 (4H, m), 4.45 (1H, d), 5.16(1H, br s), 7.19-7.31 (1H, m), 7.34-7.44 (2H, m), 7.47 (1H, d).

MS (ESI+, m/e) 534 (M+1)

Reference Example 279 1-tert-butyl3-methyl(3R,5S)-5-[{[5-(hydroxymethyl)-1-(2-methylphenyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate

¹H-NMR (CDCl₃) δ: 0.96 (6H, dd), 1.35-1.52 (9H, m), 1.67 (1H, d),2.02-2.15 (4H, m), 2.60 (1H, d), 2.75 (2H, br s), 3.28 (1H, br s), 3.57(1H, br s), 3.61-3.77 (3H, m), 4.06-4.65 (4H, m), 4.45 (1H, d), 5.16(1H, br s), 7.19-7.31 (1H, m), 7.34-7.44 (2H, m), 7.47 (1H, d).

MS (ESI+, m/e) 530 (M+1)

In the same manner as in the method shown in Reference Example 271, thefollowing compounds (Reference Examples 280-281) were obtained.

Reference Example 280 1-tert-butyl3-methyl(3R,5S)-5-[{[1-(2-fluorophenyl)-5-(phenoxymethyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate

¹H-NMR (CDCl₃) δ: 0.86-1.02 (6H, m), 1.37-1.54 (9H, m), 2.14-2.35 (1H,m), 2.47-2.63 (1H, m), 2.67 (1H, br s), 2.84 (1H, br s), 3.54 (1H, t),3.71 (3H, s), 4.35 (1H, br s), 4.91-5.07 (2H, m), 5.40 (2H, d), 6.36(2H, br s), 6.64 (2H, d), 6.91 (1H, t), 7.18 (2H, t), 7.23-7.33 (3H, m),7.42-7.58 (2H, m).

MS (ESI+, m/e) 610 (M+1)

Reference Example 281 1-tert-butyl3-methyl(3R,5S)-5-[{[1-(2-methylphenyl)-5-(phenoxymethyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate

MS (ESI+, m/e) 606 (M+1)

Reference Example 282 tert-butyl(3S,5R)-3-[{[1-(2-fluorophenyl)-5-(phenoxymethyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(hydroxymethyl)piperidine-1-carboxylate

Calcium(II) chloride (200 mg) was dissolved in ethanol (5 ml), sodiumtetrahydroborate (140 mg) was added under ice-cooling and the mixturewas stirred at 0° C. for 30 min. A solution (8 ml) of 1-tert-butyl3-methyl(3R,5S)-5-[{[1-(2-fluorophenyl)-5-(phenoxymethyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-,3-dicarboxylate (760 mg) in ethanol was added to the reaction mixtureunder ice-cooling, and the mixture was stirred at room temperature for13 hr. The reaction mixture was diluted with saturated aqueous sodiumhydrogen carbonate solution and extracted with ethyl acetate. Theextract was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The residue was subjected to silica gel column chromatography, and afraction eluted with ethyl acetate-hexane (5:95-75:25) was concentratedunder reduced pressure to give the object product (447 mg).

¹H-NMR (CDCl₃) δ: 0.85-1.01 (6H, m), 1.45 (9H, d), 1.84 (1H, br s), 2.01(1H, br s), 2.17 (1H, s), 2.44 (1H, br s), 2.72-3.38 (1H, m), 3.23-3.39(1H, m), 3.57 (3H, br s), 3.89 (1H, br s), 4.16 (1H, s), 4.33 (1H, brs), 4.28-4.86 (1H, m), 5.39 (2H, d), 6.64 (2H, d), 6.91 (1H, t), 7.18(2H, t), 7.23-7.33 (2H, m), 7.42-7.58 (2H, m).

MS (ESI+, m/e) 582 (M+1)

In the same manner as in the method shown in Reference Example 282, thefollowing compounds (Reference Examples 283-285) were obtained.

Reference Example 283 tert-butyl(3S,5R)-3-[{[1-(2-fluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(hydroxymethyl)piperidine-1-carboxylate

MS (ESI+, m/e) 562 (M+1)

Reference Example 284 tert-butyl(3S,5R)-3-[{[1-(2,3-difluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(hydroxymethyl)piperidine-1-carboxylate

MS (ESI+, m/e) 580 (M+1)

Reference Example 285 tert-butyl(3S,5R)-3-[{[1-(2,6-difluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(hydroxymethyl)piperidine-1-carboxylate

MS (ESI+, m/e) 580 (M+1)

In the same manner as in the method shown in Reference Example 270, thefollowing compound (Reference Example 286) was obtained.

Reference Example 286(3R,5S)-1-(tert-butoxycarbonyl)-5-[({5-[(2-methoxyethoxy)methyl]-(2-methylphenyl)-1H-1,2,3-triazol-4-yl}carbonyl)(2-methylpropyl)amino]piperidine-3-carboxylicacid

MS (ESI+, m/e) 588 (M+1)

Reference Example 287 tert-butyl(3R,5S)-3-(hydroxymethyl)-5-[({5-[(2-methoxyethoxy)methyl]-1-(2-methylphenyl)-1H-1,2,3-triazol-4-yl}carbonyl)(2-methylpropyl)amino]piperidine-1-carboxylate

(3R,5S)-1-(tert-Butoxycarbonyl)-5-[({5-[(2-methoxyethoxy)methyl]-1-(2-methylphenyl)-1H-1,2,3-triazol-4-yl}carbonyl)(2-methylpropyl)amino]piperidine-3-carboxylicacid (900 mg) and 1-methylmorpholine (274 μl) were dissolved in THF (5ml), ethyl chlorocarbonate (230 μl) was added under ice-cooling and themixture was stirred at 0° C. for 1 hr. Sodium tetrahydroborate (200 mg)and methanol (2 ml) were added to the reaction mixture, and the mixturewas further stirred at room temperature for 14 hr. The reaction mixturewas diluted with saturated aqueous sodium hydrogen carbonate solutionand extracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The residue was subjected to silicagel column chromatography, and a fraction eluted with ethylacetate-hexane (10:90-90:10) was concentrated under reduced pressure togive the object product (704 mg).

¹H-NMR (CDCl₃) δ: 0.88 (3H, d), 0.98 (3H, d), 1.40-1.53 (9H, m), 1.67(1H, s), 1.83 (1H, br s), 1.96-2.13 (5H, m), 2.13-2.87 (2H, m), 3.25(3H, s), 3.29-3.42 (2H, m), 3.48 (2H, d), 3.46 (2H, br s), 3.57 (3H, brs), 4.26 (2H, br s), 4.62 (2H, d), 7.26-7.40 (3H, m), 7.42-7.49 (1H, m).

MS (ESI+, m/e) 560 (M+1)

Reference Example 288 tert-butyl(3R,5S)-3-formyl-5-[({5-[(2-methoxyethoxy)methyl]-1-(2-methylphenyl)-1H-1,2,3-triazol-4-yl}carbonyl)(2-methylpropyl)amino]piperidine-1-carboxylate

tert-Butyl(3R,5S)-3-(hydroxymethyl)-5-[({5-[(2-methoxyethoxy)methyl]-1-(2-methylphenyl)-1H-1,2,3-triazol-4-yl}carbonyl)(2-methylpropyl)amino]piperidine-1-carboxylate(534 mg) and triethylamine (1.1 ml) were dissolved in DMSO, sulfurtrioxide-pyridine complex (610 mg) was added and the mixture was stirredat room temperature for 1 day. The reaction mixture was diluted withethyl acetate and washed with saturated brine. The organic layer waswashed successively with 1M hydrochloric acid and saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The residue was subjected to silica gel columnchromatography, and a fraction eluted with ethyl acetate-hexane(10:90-100:0) was concentrated under reduced pressure to give the objectproduct (377 mg).

¹H-NMR (CDCl₃) δ: 0.86-1.03 (6H, m), 1.37-1.53 (9H, m), 1.62 (2H, br s),1.97-2.14 (4H, m), 2.35-2.93 (3H, m), 3.13-3.29 (4H, m), 3.34 (2H, d),3.35 (1H, br s), 3.47 (2H, d), 3.75 (1H, br s), 4.24-4.50 (1H, m),4.57-4.73 (3H, m), 7.27-7.40 (3H, m), 7.42-7.49 (1H, m), 9.57-9.87 (1H,m).

MS (ESI+, m/e) 558 (M+1)

In the same manner as in the method shown in Reference Example 288, thefollowing compounds (Reference Examples 289-291) were obtained.

Reference Example 289 tert-butyl(3S,5R)-3-[{[1-(2-fluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-formylpiperidine-1-carboxylate

MS (ESI+, m/e) 560 (M+1)

Reference Example 290 tert-butyl(3S,5R)-3-[{[1-(2,3-difluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-formylpiperidine-1-carboxylate

MS (ESI+, m/e) 578 (M+1)

Reference Example 291 tert-butyl(3S,5R)-3-[{[1-(2,6-difluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-formylpiperidine-1-carboxylate

MS (ESI+, m/e) 578 (M+1)

Reference Example 292 tert-butyl(3R,5S)-3-(1-hydroxyethyl)-5-[({5-[(2-methoxyethoxy)methyl]-1-(2-methylphenyl)-1H-1,2,3-triazol-4-yl}carbonyl)(2-methylpropyl)amino]piperidine-1-carboxylate

tert-Butyl(3R,5S)-3-formyl-5-[({5-[(2-methoxyethoxy)methyl]-1-(2-methylphenyl)-1H-1,2,3-triazol-4-yl}carbonyl)(2-methylpropyl)amino]piperidine-1-carboxylate(360 mg) was dissolved in THF (4 ml), a solution (1M, 1.95 ml) of methylmagnesium bromide in THF was added under ice-cooling and the mixture wasstirred for 3 hr. The reaction mixture was poured into saturated aqueousammonium chloride solution, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The residue was subjected to silica gel column chromatography,and a fraction eluted with ethyl acetate-hexane (10:90-100:0) wasconcentrated under reduced pressure to give the object product (325 mg).

¹H-NMR (CDCl₃) δ 0.90 (3H, br s), 0.99 (3H, d), 1.32 (1H, d), 1.26 (3H,t), 1.37-1.54 (9H, m), 1.60-1.76 (3H, m), 1.97-2.12 (4H, m), 2.15-2.32(1H, m), 2.35-3.04 (2H, m), 3.25 (3H, s), 3.35 (2H, br s), 3.44-3.61(3H, m), 3.68 (1H, br s), 4.31 (2H, br s), 4.54-4.70 (2H, m), 7.29-7.41(3H, m), 7.42-7.49 (1H, m)

MS (ESI+, m/e) 574 (M+1)

In the same manner as in the method shown in Reference Example 292, thefollowing compounds (Reference Examples 293-299) were obtained.

Reference Example 293 tert-butyl(3S,5R)-3-[{[1-(2-fluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(1-hydroxypropyl)piperidine-1-carboxylate

MS (ESI+, m/e) 590 (M+1)

Reference Example 294 tert-butyl(3S,5R)-3-[{[1-(2-fluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(1-hydroxybutyl)piperidine-1-carboxylate

MS (ESI+, m/e) 604 (M+1)

Reference Example 295 tert-butyl(3S,5R)-3-[{[1-(2-fluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(1-hydroxy-2-methylpropyl)piperidine-1-carboxylate

MS (ESI+, m/e) 604 (M+1)

Reference Example 296 tert-butyl(3R,5S)-3-[cyclopropyl(hydroxy)methyl]-5-[{[1-(2-fluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate

MS (ESI+, m/e) 602 (M+1)

Reference Example 297 tert-butyl(3S,5R)-3-[{[1-(2-fluorophenyl)-5-(4-methoxybutyl)1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(1-hydroxypentyl)piperidine-1-carboxylate

MS (ESI+, m/e) 618 (M+1)

Reference Example 298 tert-butyl(3S,5R)-3-[{[1-(2,3-difluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(1-hydroxyethyl)piperidine-1-carboxylate

MS (ESI+, m/e) 594 (M+1)

Reference Example 299 tert-butyl(3S,5R)-3-[{[1-(2,6-difluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(1-hydroxyethyl)piperidine-1-carboxylate

MS (ESI+, m/e) 594 (M+1)

Reference Example 300 tert-butyl(3S,5R)-3-[{[1-(2-fluorophenyl)-5-(hydroxymethyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

1-tert-Butyl3-methyl(3R,5S)-5-[{[1-(2-fluorophenyl)-5-(hydroxymethyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate(1.05 g) was dissolved in THF (10 ml)-methanol (8 ml)-water (8 ml), 8Maqueous sodium hydroxide solution (6001) was added and the mixture wasstirred at 70° C. for 1.5 hr. The reaction mixture was cooled to roomtemperature and concentrated under reduced pressure. The residue wasdiluted with water, neutralized with saturated aqueous ammonium chloridesolution and extracted with ethyl acetate. The extract was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The residue, morpholine,1-hydroxybenzotriazole (150 mg) and triethylamine (7001) were dissolvedin acetonitrile (20 ml), WSC.HCL (555 mg) was added and the mixture wasstirred at room temperature for 8 hr. The reaction mixture wasconcentrated under reduced pressure, diluted with ethyl acetate andwashed with water. The organic layer was washed with saturated brine,and dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure. The residue was subjected to silica gel columnchromatography, and a fraction eluted with ethyl acetate-hexane(10:90-100:0) was concentrated under reduced pressure to give the objectproduct (764 mg).

¹H-NMR (CDCl₃) δ 0.98 (5H, dd), 0.85-1.02 (1H, m), 1.42 (6H, s), 1.49(3H, s), 2.16 (1H, d), 2.56 (1H, br s), 2.87 (2H, br s), 3.25 (1H, dd),3.47 (1H, dd), 3.53 (1H, br s), 3.59-3.76 (5H, m), 3.64 (3H, br s),4.10-4.37 (3H, m), 4.45-4.62 (2H, m), 5.14-5.30 (1H, m), 7.29-7.45 (2H,m), 7.49-7.65 (2H, m).

MS (ESI+, m/e) 589 (M+1)

In the same manner as in the method shown in Reference Example 271, thefollowing compound (Reference Example 301) was obtained.

Reference Example 301 tert-butyl(3S,5R)-3-[{[1-(2-fluorophenyl)-5-(phenoxymethyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 665 (M+1)

Reference Example 302 tert-butyl(3S,5R)-3-[{[5-(bromomethyl)-1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

To a solution (4 ml) of tert-butyl(3S,5R)-3-[{[1-(2-fluorophenyl)-5-(hydroxymethyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(410 mg) and triphenylphosphine (275 mg) in dichloromethane was addedunder ice-cooling carbon tetrabromide (350 mg), and the mixture wasstirred at room temperature for 1 hr. The reaction mixture wasconcentrated under reduced pressure, and the residue was subjected tosilica gel column chromatography, and a fraction eluted with ethylacetate-hexane (10:90-100:0) was concentrated under reduced pressure togive the object product (442 mg).

MS (ESI+, m/e) 652 (M+1)

Reference Example 303 tert-butyl(3S,5R)-3-[({5-[(diethoxyphosphoryl)methyl]-1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl}carbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

tert-Butyl(3S,5R)-3-[{[5-(bromomethyl)-1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(440 mg) was dissolved in DMF (4 ml), triethyl phosphate (295 μl) wasadded and the mixture was stirred at 110° C. for 12 hr. After cooling toroom temperature, the reaction mixture was diluted with ethyl acetateand washed with saturated brine. The organic layer was dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure to give the object product (473 mg).

MS (ESI+, m/e) 709 (M+1)

Reference Example 304 tert-butyl(3S,5R)-3-[({1-(2-fluorophenyl)-5-[(E)-2-(1,3-thiazol-2-yl)ethenyl]-1H-1,2,3-triazol-4-yl}carbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

tert-Butyl(3S,5R)-3-[({5-[(diethoxyphosphoryl)methyl]-1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl}carbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(470 mg) and 1,3-thiazole-2-carbaldehyde (90 mg) were dissolved in THF(4 ml), sodium hydride (50% in oil, 50 mg) was added under ice-coolingand the mixture was stirred at room temperature for 12 hr. The reactionmixture was diluted with saturated aqueous sodium hydrogen carbonatesolution and extracted with ethyl acetate. The extract was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The residue was subjected tosilica gel column chromatography, and a fraction eluted with ethylacetate-hexane (10:90-100:0) was concentrated under reduced pressure togive the object product (327 mg).

MS (ESI+, m/e) 668 (M+1)

Reference Example 305 tert-butyl(3S,5R)-3-[({1-(2-fluorophenyl)-5-[2-(1,3-thiazol-2-yl)ethyl]-1H-1,2,3-triazol-4-yl}carbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

tert-Butyl(3S,5R)-3-[({1-(2-fluorophenyl)-5-[(E)-2-(1,3-thiazol-2-yl)ethenyl]-1H-1,2,3-triazol-4-yl}carbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(200 mg) and 5% palladium-carbon (20 mg) were suspended in methanol (4ml), and the mixture was stirred at room temperature under a hydrogenatmosphere (1 atom) for 3 days. Insoluble material was filtered off, andthe filtrate was concentrated under reduced pressure to give the objectproduct (200 mg).

MS (ESI+, m/e) 670 (M+1)

Reference Example 306 tert-butyl(3S,5R)-3-[{[1-(2-fluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(oxirane-2-yl)piperidine-1-carboxylate

Trimethylsulfoxonium iodide (390 mg) was dissolved in DMSO (5 ml),sodium hydride (50% in oil, 85 mg) was added, and the mixture wasstirred at room temperature for 1 hr. A solution (10 ml) of tert-butyl(3S,5R)-3-[{[1-(2-fluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-formylpiperidine-1-carboxylate(656 mg) in DMSO was added to the reaction mixture, and the mixture wasfurther stirred at room temperature for 1 hr. The reaction mixture wasdiluted with saturated aqueous sodium hydrogen carbonate solution andextracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The residue was subjected to silicagel column chromatography, and a fraction eluted with ethylacetate-hexane (10:90-100:0) was concentrated under reduced pressure togive the object product (372 mg).

MS (ESI+, m/e) 574 (M+1)

Reference Example 307 tert-butyl(3S,5R)-3-[{[1-(2-fluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(1-hydroxy-2-methoxyethyl)piperidine-1-carboxylate

tert-Butyl(3S,5R)-3-[{[1-(2-fluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(oxirane-2-yl)piperidine-1-carboxylate(190 mg) was dissolved in methanol (5 ml), sodium methoxide (28%methanol solution, 320 mg) was added and the mixture was stirred at 70°C. for 8 hr. The reaction mixture was cooled to room temperature,diluted with water and extracted with ethyl acetate. The extract waswashed with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wassubjected to silica gel column chromatography, and a fraction elutedwith ethyl acetate-hexane (10:90-100:0) was concentrated under reducedpressure to give the object product (167 mg).

MS (ESI+, m/e) 606 (M+1)

In the same manner as in the method shown in Reference Example 307, thefollowing compound (Reference Example 308) was obtained.

Reference Example 308 tert-butyl(3R,5S)-3-(2-ethoxy-1-hydroxyethyl)-5-[{[1-(2-fluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate

MS (ESI+, m/e) 620 (M+1)

Reference Example 309 tert-butyl(3S,5R)-3-[{[1-(2-fluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(methoxymethyl)piperidine-1-carboxylate

tert-Butyl(3S,5R)-3-[{[1-(2-fluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(hydroxymethyl)piperidine-1-carboxylate(165 mg) and triethylamine (215 μl) were dissolved in THF (4 ml), andmethanesulfonyl chloride (60 μl) was added under ice-cooling. Themixture was stirred at 0° C. for 2 hr, and sodium methoxide (28%methanol solution, 600 mg) and methanol (2 ml) were added, and themixture was further stirred at 75° C. for 3 hr. The mixture was cooledto room temperature and diluted with water and the mixture was extractedwith ethyl acetate. The extract was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The residue was subjected to silica gel columnchromatography, and a fraction eluted with ethyl acetate-hexane(5:95-80:20) was concentrated under reduced pressure to give the objectproduct (142 mg).

MS (ESI+, m/e) 576 (M+1)

Reference Example 310 tert-butyl(3R,5S)-3-(difluoromethyl)-5-[{[1-(2-fluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate

tert-Butyl(3S,5R)-3-[{[1-(2-fluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-formylpiperidine-1-carboxylate(200 mg) was dissolved in toluene (4 ml), and diethylaminosulfurtrifluoride (240 μl) was added under ice-cooling. The mixture wasstirred at room temperature for 3 days and diluted with saturatedaqueous ammonium chloride solution and the mixture was extracted withethyl acetate. The extract was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The residue was subjected to silica gel columnchromatography, and a fraction eluted with ethyl acetate-hexane(5:95-80:20) was concentrated under reduced pressure to give the objectproduct (45 mg).

MS (ESI+, m/e) 582 (M+1)

In the same manner as in the method shown in Reference Example 271, thefollowing compound (Reference Example 311) was obtained.

Reference Example 311 tert-butyl(3S,5R)-3-[({5-[(4-fluorophenoxy)methyl]-1-phenyl-1H-1,2,3-triazol-4-yl}carbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 665 (M+1)

In the same manner as in the method shown in Reference Example 265, thefollowing compounds (Reference Examples 312-318) were obtained.

Reference Example 3121-(2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid

¹H-NMR (CDCl₃) δ 3.13 (3H, s), 7.29-7.43 (2H, m), 7.43-7.55 (1H, m),7.56-7.70 (1H, m).

MS (ESI+, m/e) 222 (M+1)

Reference Example 3135-ethyl-1-(2-fluorophenyl)-1H-1,2,3-triazole-4-carboxylic acid

¹H-NMR (CDCl₃) δ 1.16 (3H, t), 2.96 (2H, q), 7.29-7.43 (2H, m),7.43-7.55 (1H, m), 7.56-7.70 (1H, m).

MS (ESI+, m/e) 236 (M+1)

Reference Example 3141-(2-fluorophenyl)-5-propyl-1H-1,2,3-triazole-4-carboxylic acid

¹H-NMR (CDCl₃) δ 0.84 (3H, t), 1.44-1.67 (2H, m), 2.84-3.09 (2H, m),7.29-7.54 (3H, m), 7.56-7.70 (1H, m).

MS (ESI+, m/e) 250 (M+1)

Reference Example 3151-(2-fluorophenyl)-5-(1-methylethyl)-1H-1,2,3-triazole-4-carboxylic acid

¹H-NMR (CDCl₃) δ 1.11-1.49 (6H, m), 3.14-3.39 (1H, m), 7.27-7.54 (3H,m), 7.54-7.71 (1H, m).

MS (ESI+, m/e) 250 (M+1)

Reference Example 3165-butyl-1-(2-fluorophenyl)-1H-1,2,3-triazole-4-carboxylic acid

¹H-NMR (CDCl₃) δ 1.10 (3H, t), 1.23-1.90 (4H, m), 2.89-3.00 (2H, m),7.29-7.43 (2H, m), 7.43-7.55 (1H, m), 7.56-7.70 (1H, m).

MS (ESI+, m/e) 264 (M+1)

Reference Example 3171-(2-fluorophenyl)-5-[(methylsulfanyl)methyl]-1H-1,2,3-triazole-4-carboxylicacid

¹H-NMR (CDCl₃) δ 2.01 (3H, s), 4.06 (2H, s), 7.28-7.45 (2H, m),7.52-7.68 (2H, m).

MS (ESI+, m/e) 268 (M+1)

Reference Example 3181-(2-fluorophenyl)-5-(3,3,3-trifluoropropyl)-1H-1,2,3-triazole-4-carboxylicacid

¹H-NMR (CDCl₃) δ 2.50 (2H, dt), 3.11-3.21 (2H, m), 7.32-7.47 (2H, m),7.47-7.58 (1H, m), 7.59-7.74 (1H, m).

MS (ESI+, m/e) 304 (M+1)

In the same manner as in the method shown in Reference Example 235, thefollowing compounds (Reference Examples 319-323) were obtained.

Reference Example 319 tert-butyl(3S,5R)-3-[{[1-(2-fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 573 (M+1)

Reference Example 320 tert-butyl(3S,5R)-3-[{[5-ethyl-1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

¹H-NMR (CDCl₃) δ 0.85 (2H, br s), 0.98 (4H, dd), 1.03-1.18 (3H, m), 1.41(6H, s), 1.48 (3H, br s), 1.85-2.25 (2H, m), 2.46 (1H, br s), 2.65-2.89(6H, m), 2.96 (1H, br s), 3.23 (1H, br s), 3.40 (1H, br s), 3.68 (6H, brs), 4.06-4.34 (2H, m), 4.66 (1H, br s), 7.28-7.51 (3H, m), 7.60 (1H, d).

MS (ESI+, m/e) 587 (M+1)

Reference Example 321 tert-butyl(3S,5R)-3-[{[1-(2-fluorophenyl)-5-propyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

¹H-NMR (CDCl₃) δ 0.69-0.92 (5H, m), 0.97 (4H, dd), 1.32-1.55 (11H, m),1.79-2.11 (2H, m), 2.18 (1H, br s), 2.44 (1H, br s), 2.64-3.03 (5H, m),3.23 (1H, br s), 3.39 (1H, d), 3.68 (8H, br s), 4.06-4.31 (1H, m), 4.63(1H, br s), 7.28-7.51 (3H, m), 7.61 (1H, br s).

MS (ESI+, m/e) 601 (M+1)

Reference Example 322 tert-butyl(3S,5R)-3-[{[1-(2-fluorophenyl)-5-(1-methylethyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

¹H-NMR (CDCl₃) δ 0.72-0.93 (2H, m), 0.99 (4H, dd), 1.16-1.35 (6H, m),1.35-1.56 (9H, m), 1.93-2.13 (2H, m), 2.23 (1H, d), 2.45 (1H, br s),2.61-2.95 (6H, m), 2.95-3.22 (1H, m), 3.34 (2H, br s), 3.51-3.87 (6H,m), 4.12 (1H, br s), 7.28-7.51 (3H, m), 7.54-7.67 (1H, m).

MS (ESI+, m/e) 601 (M+1)

Reference Example 323 tert-butyl(3S,5R)-3-[{[5-butyl-1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 615 (M+1)

Reference Example 324 1-tert-butyl3-methyl(3R,5S)-5-[({1-(2-fluorophenyl)-5-[(methylsulfanyl)methyl]-1H-1,2,3-triazol-4-yl}carbonyl)(2-methylpropyl)amino]piperidine-1,3-dicarboxylate

1-(2-Fluorophenyl)-5-[(methylsulfanyl)methyl]-1H-1,2,3-triazole-4-carboxylicacid (960 mg), 1-tert-butyl 3-methyl(3R,5S)-5-(isobutylamino)piperidine-1,3-dicarboxylate (1.15 g) andN,N-diisopropylethylamine (1.6 μl) were dissolved in 1,2-dichloroethane(10 ml), chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate(1.50 g) was added and the mixture was stirred at room temperature for 3days. The reaction mixture was diluted with saturated aqueous sodiumhydrogen carbonate solution and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The residue was subjected to silica gel column chromatography,and a fraction eluted with ethyl acetate-hexane (10:90-100:0) wasconcentrated under reduced pressure to give the object product (1.60 g).

¹H-NMR (CDCl₃) δ 0.95 (6H, dd), 1.36-1.53 (9H, m), 1.90-2.05 (5H, m),2.14-2.31 (1H, m), 2.40-2.95 (3H, m), 3.30 (1H, d), 3.46-3.62 (1H, m),3.71 (3H, s), 3.88-4.02 (2H, m), 4.17-4.82 (2H, m), 4.30 (1H, br s),7.25-7.41 (2H, m), 7.48-7.65 (2H, m).

MS (ESI+, m/e) 564 (M+1)

In the same manner as in the method shown in Reference Example 324, thefollowing compound (Reference Example 325) was obtained.

Reference Example 325 1-tert-butyl3-methyl(3R,5S)-5-[{[1-(2-fluorophenyl)-5-(3,3,3-trifluoropropyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate

¹H-NMR (CDCl₃) δ 0.85-1.02 (6H, m), 1.46 (7H, d), 1.46 (2H, br s),1.78-2.02 (1H, m), 2.09-2.76 (5H, m), 2.85 (1H, d), 2.97-3.11 (2H, m),3.21-3.37 (1H, m), 3.39-3.66 (1H, m), 3.71 (3H, s), 3.76-4.02 (1H, m),4.16-4.94 (2H, m), 4.25 (1H, br s), 7.39 (2H, t), 7.47 (1H, t), 7.62(1H, ddd).

MS (ESI+, m/e) 600 (M+1)

In the same manner as in the method shown in Reference Example 300, thefollowing compounds (Reference Examples 326-327) were obtained.

Reference Example 326 tert-butyl(3S,5R)-3-[({1-(2-fluorophenyl)-5-[(methylsulfanyl)methyl]-1H-1,2,3-triazol-4-yl}carbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

¹H-NMR (CDCl₃) δ 0.85-1.01 (6H, m), 1.48 (1H, br s), 1.42 (8H, s), 1.99(3H, s), 2.16 (1H, d), 2.47 (1H, br s), 2.78-2.94 (3H, m), 3.18-3.32(1H, m), 3.32-3.44 (1H, m), 3.59-3.75 (9H, m), 3.93 (2H, d), 3.87 (1H,br s), 4.19-4.32 (1H, m), 4.71 (1H, br s), 7.37 (2H, t), 7.56 (2H, ddd).

MS (ESI+, m/e) 619 (M+1)

Reference Example 327 tert-butyl(3S,5R)-3-[{[1-(2-fluorophenyl)-5-(3,3,3-trifluoropropyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

¹H-NMR (CDCl₃) δ 0.87 (2H, d), 0.97 (4H, d), 1.37-1.53 (9H, m),2.03-2.19 (2H, m), 2.36 (1H, br s), 2.45 (2H, br s), 2.82 (3H, br s),3.06 (1H, d), 3.03 (1H, br s), 3.19-3.35 (1H, m), 3.43 (1H, dd),3.59-3.76 (5H, m), 3.64 (3H, br s), 3.90-4.20 (2H, m), 4.74 (1H, br s),7.33-7.50 (3H, m), 7.55-7.72 (1H, m).

MS (ESI+, m/e) 655 (M+1)

Reference Example 328 ethyl1-(2-fluorophenyl)-1H-1,2,3-triazole-4-carboxylate

1-Azido-2-fluorobenzene (1.0 g) and ethyl propiolate (2.2 g) weredissolved in toluene (12 ml) and the mixture was stirred at 100° C. for13 hr. After cooling to room temperature, the reaction mixture wasconcentrated under reduced pressure. The residue was subjected to silicagel column chromatography, and a fraction eluted with ethylacetate-hexane (10:90-80:20) was concentrated under reduced pressure togive the object product (111 mg).

MS (ESI+, m/e) 235 (M+1)

Reference Example 329 1-(2-fluorophenyl)-1H-1,2,3-triazole-4-carboxylicacid

Ethyl 1-(2-fluorophenyl)-1H-1,2,3-triazole-4-carboxylate (110 mg) wasdissolved in ethanol (3 ml)-water (2 ml)-1M aqueous sodium hydroxidesolution (1 ml) and the mixture was stirred at 60° C. for 12 hr. Aftercooling to room temperature, the reaction mixture was concentrated underreduced pressure. The residue was diluted with water, neutralized (pH:2) with 1M hydrochloric acid, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure to give the object product (92 mg).

MS (ESI+, m/e) 208 (M+1)

In the same manner as in the method shown in Reference Example 235, thefollowing compound (Reference Example 330) was obtained.

Reference Example 330 tert-butyl(3S,5R)-3-[{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

¹H-NMR (CDCl₃) δ 0.86-1.02 (6H, m), 1.40 (6H, br s), 1.48 (3H, br s),2.01-2.18 (2H, m), 2.77-2.94 (6H, m), 3.13-3.51 (1H, m), 3.58-3.74 (6H,m), 3.88-5.22 (4H, m), 7.28-7.42 (2H, m), 7.42-7.56 (1H, m), 7.77-8.05(1H, m), 8.59 (1H, br s).

MS (ESI+, m/e) 559 (M+1)

Reference Example 331 tert-butyl(3S,5R)-3-[{[1-(2-fluorophenyl)-5-(methoxymethyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

tert-Butyl(3S,5R)-3-[{[1-(2-fluorophenyl)-5-(hydroxymethyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(210 mg) and triethylamine (150 μl) were dissolved in THF (4 ml), andmethanesulfonyl chloride (45 μl) was added under ice-cooling. Themixture was stirred at 0° C. for 4 hr, sodium methoxide (28% methanolsolution, 350 mg) and methanol (4 ml) were added and the mixture wasstirred at room temperature for 2 hr. The reaction mixture was dilutedwith water and extracted with ethyl acetate. The extract was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The residue was subjected tosilica gel column chromatography, and a fraction eluted with ethylacetate-hexane (10:90-100:0) was concentrated under reduced pressure togive the object product (195 mg).

¹H-NMR (CDCl₃) δ 0.86 (2H, d), 0.97 (4H, dd), 1.42 (6H, s), 1.48 (3H,s), 2.17 (2H, br s), 2.67-3.06 (3H, m), 3.16-3.25 (4H, m), 3.29 (1H, brs), 3.33-3.56 (2H, m), 3.72 (4H, s), 3.68 (4H, s), 4.19-4.33 (1H, m),4.51-4.81 (3H, m), 7.28-7.44 (2H, m), 7.47-7.65 (2H, m).

MS (ESI+, m/e) 603 (M+1)

Reference Example 332 tert-butyl(3S,5R)-3-[({1-(2-fluorophenyl)-5-[(2-methoxyethoxy)methyl]-1H-1,2,3-triazol-4-yl}carbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

tert-Butyl(3S,5R)-3-[{[1-(2-fluorophenyl)-5-(hydroxymethyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(510 mg) and triethylamine (365 μl) were dissolved in THF (8 ml), andmethanesulfonyl chloride (110 μl) was added under ice-cooling. Themixture was stirred at 0° C. for 3 hr, 2-methoxyethanol (200 mg) wasadded and the mixture was stirred at room temperature for 14 hr. Thereaction mixture was diluted with water and extracted with ethylacetate. The extract was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The residue was subjected to silica gel column chromatography,and a fraction eluted with ethyl acetate-hexane (10:90-100:0) wasconcentrated under reduced pressure to give the object product (491 mg).

¹H-NMR (CDCl₃) δ 0.87 (2H, d), 0.97 (4H, dd), 1.33-1.54 (9H, m),1.85-2.22 (2H, m), 2.49 (1H, br s), 2.80 (2H, br s), 2.99 (1H, br s),3.13-3.41 (6H, m), 3.41-3.58 (3H, m), 3.58-3.90 (8H, m), 4.10-4.22 (1H,m), 4.28 (1H, br s), 4.64 (1H, br s), 4.76-4.96 (2H, m), 7.28-7.40 (2H,m), 7.47-7.63 (2H, m).

MS (ESI+, m/e) 647 (M+1)

In the same manner as in the method shown in Reference Example 270, thefollowing compound (Reference Example 333) was obtained.

Reference Example 333 tert-butyl(3S,5R)-3-[({5-[(2,2-difluoroethoxy)methyl]-1-phenyl-1H-1,2,3-triazol-4-yl}carbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 635 (M+1)

In the same manner as in the method shown in Reference Example 235, thefollowing compound (Reference Example 334) was obtained.

Reference Example 334 tert-butyl(3S,5R)-3-{[(5-cyclopropyl-1-phenyl-1H-1,2,3-triazol-4-yl)carbonyl](2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 581 (M+1)

Reference Example 335 tert-butyl(3S,5R)-3-[{[1-(2-fluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(1,3-oxazol-5-yl)piperidine-1-carboxylate

tert-Butyl(3S,5R)-3-[{[1-(2-fluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-formylpiperidine-1-carboxylate(235 mg) and tosylmethyl isocyanide (125 mg) were dissolved in methanol(4 ml), sodium methoxide (28% methanol solution, 325 mg) was added andthe mixture was heated under reflux with stirring for 2 hr. The mixturewas cooled to room temperature, diluted with water and extracted withethyl acetate. The extract was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The residue was subjected to silica gel columnchromatography, and a fraction eluted with ethyl acetate-hexane(5:95-100:0) was concentrated under reduced pressure to give the objectproduct (98.5 mg).

¹H-NMR (CDCl₃) δ 0.90 (3H, br s), 0.99 (3H, d), 1.40-1.57 (13H, m), 1.71(2H, br s), 1.92-2.07 (1H, m), 2.13-2.37 (1H, m), 2.68 (2H, d), 2.83(2H, d), 2.90-3.07 (1H, m), 3.17-3.31 (5H, m), 3.48-4.05 (2H, m),4.13-4.91 (2H, m), 6.86 (1H, s), 7.36 (2H, t), 7.47 (1H, t), 7.58 (1H,td), 7.81 (1H, s).

MS (ESI+, m/e) 599 (M+1)

In the same manner as in the method shown in Reference Example 335, thefollowing compound (Reference Example 336) was obtained.

Reference Example 336 tert-butyl(3S)-3-[{[1-(2-fluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(1,3-oxazol-5-yl)piperidine-1-carboxylate

MS (ESI+, m/e) 599 (M+1)

In the same manner as in the method shown in Example 147, the compoundsdescribed in the following Examples 164-168 were obtained.

Example 1641-(2-fluorophenyl)-5-[(2-methoxyethoxy)methyl]-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-1,2,3-triazole-4-carboxamidehydrochloride

MS (ESI+, m/e) 547 (M+1)

Example 1651-(2-fluorophenyl)-5-(4-methoxybutyl)-N-[(3S,5R)-5-(methoxymethyl)piperidin-3-yl]-N-(2-methylpropyl)-1H-1,2,3-triazole-4-carboxamidehydrochloride

MS (ESI+, m/e) 476 (M+1)

Example 1661-(2-fluorophenyl)-5-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(1,3-oxazol-5-yl)piperidin-3-yl]-1H-1,2,3-triazole-4-carboxamidehydrochloride

MS (ESI+, m/e) 499 (M+1)

Example 1671-(2-fluorophenyl)-5-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S)-5-(1,3-oxazol-5-yl)piperidin-3-yl]-1H-1,2,3-triazole-4-carboxamidehydrochloride

MS (ESI+, m/e) 499 (M+1)

Example 1685-cyclopropyl-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1-phenyl-1H-1,2,3-triazole-4-carboxamidehydrochloride

MS (ESI+, m/e) 481 (M+1)

In the same manner as in the method shown in Example 161, the compounddescribed in the following Example 169 was obtained.

Example 169N-[(3S,5R)-5-(difluoromethyl)piperidin-3-yl]-1-(2-fluorophenyl)-5-(4-methoxybutyl)-N-(2-methylpropyl)-1H-1,2,3-triazole-4-carboxamide½ fumarate

MS (ESI+, m/e) 482 (M+1)

Example 1701-(2-fluorophenyl)-N-[(3S,5R)-5-(hydroxymethyl)piperidin-3-yl]-5-(4-methoxybutyl)-N-(2-methylpropyl)-1H-1,2,3-triazole-4-carboxamidehydrochloride

tert-Butyl(3S,5R)-3-[{[1-(2-fluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(hydroxymethyl)piperidine-1-carboxylate(400 mg) was dissolved in 10% hydrogen chloride-methanol (4 ml), and themixture was stirred at room temperature for 18 hr. The reaction mixturewas concentrated to give the object product (334 mg).

MS (ESI+, m/e) 462 (M+1)

In the same manner as in the method shown in Example 170, the compoundsdescribed in the following Examples 171-173 were obtained.

Example 1711-(2-fluorophenyl)-N-[(3S,5R)-5-(hydroxymethyl)piperidin-3-yl]-N-(2-methylpropyl)-5-(phenoxymethyl)-1H-1,2,3-triazole-4-carboxamidehydrochloride

MS (ESI+, m/e) 482 (M+1)

Example 1721-(2,3-difluorophenyl)-N-[(3S,5R)-5-(hydroxymethyl)piperidin-3-yl]-5-(4-methoxybutyl)-N-(2-methylpropyl)-1H-1,2,3-triazole-4-carboxamidehydrochloride

MS (ESI+, m/e) 480 (M+1)

Example 1731-(2,6-difluorophenyl)-N-[(3S,5R)-5-(hydroxymethyl)piperidin-3-yl]-5-(4-methoxybutyl)-N-(2-methylpropyl)-1H-1,2,3-triazole-4-carboxamidehydrochloride

MS (ESI+, m/e) 480 (M+1)

Example 174N-[(3S,5R)-5-(1-hydroxyethyl)piperidin-3-yl]-5-[(2-methoxyethoxy)methyl]-1-(2-methylphenyl)-N-(2-methylpropyl)-1H-1,2,3-triazole-4-carboxamide½ fumarate

tert-Butyl(3R,5S)-3-(1-hydroxyethyl)-5-[({5-[(2-methoxyethoxy)methyl]-1-(2-methylphenyl)-1H-1,2,3-triazol-4-yl}carbonyl)(2-methylpropyl)amino]piperidine-1-carboxylate(319 mg) was dissolved in 10% hydrogen chloride-methanol (4 ml), and themixture was stirred at room temperature for 13 hr. The reaction mixturewas concentrated under reduced pressure, and the residue was subjectedto reversed-phase preparative HPLC and the eluted fraction wasconcentrated under reduced pressure. The residual aqueous layer wasneutralized with 3.5M aqueous potassium carbonate solution and extractedwith ethyl acetate. The extract was dried over anhydrous magnesiumsulfate, and the solvent was concentrated under reduced pressure. Theresidue and fumaric acid (27.9 mg) were dissolved in methanol (2 ml),and the solvent was evaporated under reduced pressure to give the objectproduct (254 mg).

MS (ESI+, m/e) 474 (M+1)

In the same manner as in the method shown in Example 174, the compoundsdescribed in the following Examples 175-184 were obtained.

Example 1751-(2-fluorophenyl)-5-(hydroxymethyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-1,2,3-triazole-4-carboxamide½ fumarate

MS (ESI+, m/e) 489 (M+1)

Example 1761-(2-fluorophenyl)-N-[(3S,5R)-5-(1-hydroxy-2-methoxyethyl)piperidin-3-yl]-5-(4-methoxybutyl)-N-(2-methylpropyl)-1H-1,2,3-triazole-4-carboxamide½ fumarate

MS (ESI+, m/e) 506 (M+1)

Example 177N-[(3S,5R)-5-(2-ethoxy-1-hydroxyethyl)piperidin-3-yl]-(2-fluorophenyl)-5-(4-methoxybutyl)-N-(2-methylpropyl)-1H-1,2,3-triazole-4-carboxamide½ fumarate

MS (ESI+, m/e) 520 (M+1)

Example 1781-(2,3-difluorophenyl)-N-[(3S,5R)-5-(1-hydroxyethyl)piperidin-3-yl]-5-(4-methoxybutyl)-N-(2-methylpropyl)-1H-1,2,3-triazole-4-carboxamide½ fumarate

MS (ESI+, m/e) 494 (M+1)

Example 1791-(2,6-difluorophenyl)-N-[(3S,5R)-5-(1-hydroxyethyl)piperidin-3-yl]-5-(4-methoxybutyl)-N-(2-methylpropyl)-1H-1,2,3-triazole-4-carboxamide½ fumarate

MS (ESI+, m/e) 494 (M+1)

Example 180N-{(3S,5R)-5-[cyclopropyl(hydroxy)methyl]piperidin-3-yl}-1-(2-fluorophenyl)-5-(4-methoxybutyl)-N-(2-methylpropyl)-1H-1,2,3-triazole-4-carboxamide½ fumarate

MS (ESI+, m/e) 502 (M+1)

Example 1811-(2-fluorophenyl)-N-[(3S,5R)-5-(1-hydroxypropyl)piperidin-3-yl]-5-(4-methoxybutyl)-N-(2-methylpropyl)-1H-1,2,3-triazole-4-carboxamide½ fumarate

MS (ESI+, m/e) 490 (M+1)

Example 1821-(2-fluorophenyl)-N-[(3S,5R)-5-(1-hydroxybutyl)piperidin-3-yl]-5-(4-methoxybutyl)-N-(2-methylpropyl)-1H-1,2,3-triazole-4-carboxamide½ fumarate

MS (ESI+, m/e) 504 (M+1)

Example 1831-(2-fluorophenyl)-N-[(3S,5R)-5-(1-hydroxy-2-methylpropyl)piperidin-3-yl]-5-(4-methoxybutyl)-N-(2-methylpropyl)-1H-1,2,3-triazole-4-carboxamide½ fumarate

MS (ESI+, m/e) 504 (M+1)

Example 1841-(2-fluorophenyl)-N-[(3S,5R)-5-(1-hydroxypentyl)piperidin-3-yl]-5-(4-methoxybutyl)-N-(2-methylpropyl)-1H-1,2,3-triazole-4-carboxamide½ fumarate

MS (ESI+, m/e) 518 (M+1)

Example 1851-(2-fluorophenyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-5-(phenoxymethyl)-1H-1,2,3-triazole-4-carboxamide½ fumarate

tert-Butyl(3S,5R)-3-[{[1-(2-fluorophenyl)-5-(phenoxymethyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(119 mg) was dissolved in 1M hydrogen chloride-ethyl acetate (4 ml), andthe mixture was stirred at room temperature for 13 hr and concentratedunder reduced pressure. The residue was diluted with ethyl acetate,washed successively with 3.5M aqueous potassium carbonate solution andsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The residue was subjected tobasic silica gel column chromatography, and a fraction eluted with ethylacetate-hexane-methanol (10:90:0-100:0:0-85:0:15) was concentrated underreduced pressure. The residue was dissolved in methanol (2 ml), fumaricacid (7.9 mg) was added and the mixture was stirred at room temperaturefor 1 hr. The reaction mixture was concentrated under reduced pressureto give the object product (87 mg).

MS (ESI+, m/e) 565 (M+1)

In the same manner as in the method shown in Example 185, the compoundsdescribed in the following Examples 186-197 were obtained.

Example 1861-(2-fluorophenyl)-5-[(2-methoxyethoxy)methyl]-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-1,2,3-triazole-4-carboxamide½ fumarate

MS (ESI+, m/e) 547 (M+1)

Example 1871-(2-fluorophenyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-5-[2-(1,3-thiazol-2-yl)ethyl]-1H-1,2,3-triazole-4-carboxamide½ fumarate

MS (ESI+, m/e) 570 (M+1)

Example 1885-[(4-fluorophenoxy)methyl]-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1-phenyl-1H-1,2,3-triazole-4-carboxamide½ fumarate

MS (ESI+, m/e) 565 (M+1)

Example 1891-(2-fluorophenyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-1,2,3-triazole-4-carboxamide½ fumarate

MS (ESI+, m/e) 459 (M+1)

Example 1901-(2-fluorophenyl)-5-methyl-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-1,2,3-triazole-4-carboxamide½ fumarate

MS (ESI+, m/e) 473 (M+1)

Example 1915-ethyl-1-(2-fluorophenyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-1,2,3-triazole-4-carboxamide½ fumarate

MS (ESI+, m/e) 487 (M+1)

Example 1921-(2-fluorophenyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-5-propyl-1H-1,2,3-triazole-4-carboxamide½ fumarate

MS (ESI+, m/e) 501 (M+1)

Example 1935-butyl-1-(2-fluorophenyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-1,2,3-triazole-4-carboxamide½ fumarate

MS (ESI+, m/e) 515 (M+1)

Example 1941-(2-fluorophenyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-5-(3,3,3-trifluoropropyl)-1H-1,2,3-triazole-4-carboxamide½ fumarate

MS (ESI+, m/e) 555 (M+1)

Example 1951-(2-fluorophenyl)-N-(2-methylpropyl)-5-[(methylsulfanyl)methyl]-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-1,2,3-triazole-4-carboxamide½ fumarate

MS (ESI+, m/e) 519 (M+1)

Example 1961-(2-fluorophenyl)-5-(methoxymethyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-1,2,3-triazole-4-carboxamide½ fumarate

MS (ESI+, m/e) 503 (M+1)

Example 1971-(2-fluorophenyl)-5-(1-methylethyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-1,2,3-triazole-4-carboxamide½ fumarate

MS (ESI+, m/e) 501 (M+1)

Example 1985-[(2,2-difluoroethoxy)methyl]-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1-phenyl-1H-1,2,3-triazole-4-carboxamide

tert-Butyl(3S,5R)-3-[({5-[(2,2-difluoroethoxy)methyl]-1-phenyl-1H-1,2,3-triazol-4-yl}carbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(15.0 mg) was dissolved in 1M hydrogen chloride-ethyl acetate (3 ml),and the mixture was stirred at room temperature for 3 hr. The reactionmixture was concentrated under reduced pressure, the residue wassubjected to reversed-phase preparative HPLC and the eluted fraction wasconcentrated under reduced pressure. The residual aqueous layer wasneutralized with 3.5M aqueous potassium carbonate solution and extractedwith ethyl acetate. The extract was dried over anhydrous magnesiumsulfate, and the solvent was evaporated under reduced pressure to givethe object product (3.6 mg).

MS (ESI+, m/e) 535 (M+1)

Reference Example 337 methyl5-(2-methoxyphenyl)-1H-pyrrole-2-carboxylate

28%-Sodium metholate-methanol solution (4.4 ml) was diluted withmethanol (5 ml), and cooled to −20° C. A solution of(2E)-3-(2-methoxyphenyl)prop-2-enal (2.4 g) and ethyl azidoacetate (7.5g) in methanol (8 ml) was added over 30 min, and the mixture was stirredat −10° C. for 1 hr and at room temperature for 2 hr. The reactionmixture was poured into water and extracted with ether. The extract waswashed with brine, and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure. The residue was subjected tosilica gel column chromatography, and a fraction eluted with ethylacetate-hexane (1:4) was concentrated under reduced pressure to givemethyl (2Z,4E)-2-azido-5-(2-methoxyphenyl)penta-2,4-dienoate (3.6 g). Apart (3.5 g) thereof was dissolved in chloroform (10 ml), zinc iodide(214 mg) was added and the mixture was stirred at room temperature for12 hr. The reaction mixture was poured into water, and extracted with1,2-dichloroethane. The extract was dried over anhydrous sodium sulfateand the solvent was evaporated under reduced pressure. The residue wassubjected to silica gel column chromatography, and a fraction elutedwith ethyl acetate-hexane (1:4) was concentrated under reduced pressureto give the object product (3.26 g).

¹H-NMR (CDCl₃) δ 3.88 (3H, s), 4.00 (3H, s), 6.57-6.66 (1H, m),6.90-7.06 (3H, m), 7.20-7.29 (1H, m), 7.68 (1H, d), 10.41 (1H, br s)

Reference Example 338 ethyl1-(4-methoxybutyl)-5-phenyl-1H-pyrrole-2-carboxylate

Ethyl 5-phenyl-1H-pyrrole-2-carboxylate (400 mg) and 4-methoxybutylmethanesulfonate (440 mg) were dissolved in DMF (10 ml), cesiumcarbonate (780 mg) was added and the mixture was stirred at 60° C. for12 hr. The reaction mixture was poured into water and the mixture wasextracted with ethyl acetate. The extract was washed with brine, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure. The residue was subjected to silica gel columnchromatography, and a fraction eluted with ethyl acetate-hexane(1:9-1:4) was concentrated under reduced pressure to give the objectproduct (430 mg).

¹H-NMR (CDCl₃) δ 1.31-1.47 (2H, m), 1.61-1.76 (2H, m), 3.21 (2H, t),3.22-3.23 (3H, m), 3.83 (3H, s), 6.15 (1H, d), 7.03 (1H, d), 7.34-7.48(5H, m).

In the same manner as in Reference Example 338, the following compounds(Reference Examples 340-343) were synthesized.

Reference Example 339 ethyl1-(4-methoxybutyl)-5-(1-methylethyl)-1H-pyrrole-2-carboxylate

¹H-NMR (CDCl₃) δ 1.18-1.41 (9H, m), 1.55-1.83 (4H, m), 1.56-1.85 (3H,m), 2.95 (1H, dt), 3.28-3.47 (5H, m), 4.18-4.39 (4H, m), 5.99 (1H, t),6.95 (1H, d).

Reference Example 340 methyl1-(4-methoxybutyl)-5-(thiophen-2-yl)-1H-pyrrole-2-carboxylate

¹H-NMR (CDCl₃) δ 1.48-1.63 (2H, m), 1.81 (1H, m), 3.25-3.38 (3H, m),3.27-3.35 (5H, m), 3.84 (3H, s), 4.46 (2H, d), 6.28 (1H, d), 7.00 (1H,d), 7.08-7.13 (2H, m), 7.39 (1H, dd)

Reference Example 341 methyl1-(4-methoxybutyl)-5-(2-methoxyphenyl)-1H-pyrrole-2-carboxylate

¹H-NMR (CDCl₃) δ 1.21-1.44 (2H, m), 1.54-1.69 (2H, m), 3.20 (3H, s),3.16 (1H, t), 3.80 (3H, s), 3.83 (3H, s), 4.18 (2H, t), 4.25-4.41 (2H,m), 6.09 (1H, d), 6.93-7.13 (3H, m), 7.20-7.49 (2H, m)

Reference Example 342 methyl 1-(4-methoxybutyl)-1H-pyrrole-2-carboxylate

¹H-NMR (CDCl₃) δ 1.57 (2H, dd), 1.77-1.91 (2H, m), 3.32 (3H, s), 3.38(2H, t), 3.81 (3H, s), 4.34 (2H, t), 6.09-6.14 (1H, m), 6.83-6.87 (1H,m), 6.95 (1H, dd)

Reference Example 343 methyl5-formyl-1-(4-methoxybutyl)-1H-pyrrole-2-carboxylate

¹H-NMR (CDCl₃) δ 1.54-1.69 (2H, m), 1.70-1.90 (2H, m), 3.33 (3H, s),3.40 (2H, t), 3.88 (3H, s), 4.84 (2H, d), 6.86-6.96 (2H, m), 9.71 (1H,s)

Reference Example 344 methyl 5-bromo-1H-pyrrole-2-carboxylate

Methyl 1-(4-methoxybutyl)-1H-pyrrole-2-carboxylate (4.5 g) was dissolvedin dichloromethane (30 ml), N-bromosuccinimide (4.0 g) was added and themixture was stirred for 1 hr. The reaction mixture was washedsuccessively with water and brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure. The residuewas subjected to silica gel column chromatography, and a fraction elutedwith ethyl acetate-hexane (1:4) was concentrated under reduced pressureto give the object product (2.2 g).

¹H-NMR (CDCl₃) δ 1.62 (2H, dd), 1.70-1.85 (2H, m), 3.33 (3H, s), 3.39(2H, t), 3.80 (3H, s), 4.38-4.50 (2H, m), 6.19 (1H, d), 6.94 (1H, d)

Reference Example 3451-(4-methoxybutyl)-5-phenyl-1H-pyrrole-2-carboxylic acid

Ethyl 1-(4-methoxybutyl)-5-phenyl-1H-pyrrole-2-carboxylate (430 mg) wasdissolved in methanol (2 ml), 2M aqueous sodium hydroxide solution (4ml) was added and the mixture was stirred at 60° C. for 12 hr. Thereaction mixture was concentrated under reduced pressure, and theaqueous layer of the mixture was adjusted to pH 3 with 6M hydrochloricacid, and the mixture was extracted with ethyl acetate. The extract waswashed with brine, and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure to give the object product (420mg).

¹H-NMR (DMSO-d₆) δ: 1.11-1.27 (2H, m), 1.44-1.60 (2H, m), 3.01-3.13 (5H,m), 4.31 (2H, t), 6.15 (1H, d), 6.91 (1H, d), 7.34-7.50 (5H, m), 12.15(1H, s)

In the same manner as in Reference Example 345, the following compounds(Reference Examples 346-349) were synthesized.

Reference Example 3461-(4-methoxybutyl)-5-(1-methylethyl)-1H-pyrrole-2-carboxylic acid

¹H-NMR (CDCl₃) δ 1.53-1.83 (4H, m), 2.94 (1H, m), 3.25-3.46 (5H, m),4.27 (2H, dd), 5.88-6.10 (1H, m), 6.95 (1H, t), 8.9 (1H, br)

Reference Example 3471-(4-methoxybutyl)-5-(thiophen-2-yl)-1H-pyrrole-2-carboxylic acid

¹H-NMR (CDCl₃) δ 1.55 (2H, d), 1.73-1.88 (3H, m), 3.22-3.39 (3H, m),4.42 (2H, d), 6.29 (1H, d), 7.11 (3H, d), 7.39 (1H, dd)

Reference Example 3481-(4-methoxybutyl)-5-(2-methoxyphenyl)-1H-pyrrole-2-carboxylic acid

¹H-NMR (CDCl₃) δ 1.21-1.42 (2H, m), 1.57-1.72 (1H, m), 3.18 (5H, t),3.81 (3H, s), 4.20 (2H, t), 6.13 (1H, d), 6.94-7.09 (2H, m), 7.20-7.30(2H, m), 7.42 (1H, dd)

Reference Example 349 5-bromo-1-(4-methoxybutyl)-1H-pyrrole-2-carboxylicacid

¹H-NMR (CDCl₃) δ 1.56-1.70 (2H, m), 1.72-1.88 (2H, m), 3.34 (3H, s),3.41 (2H, t), 4.38-4.55 (2H, m), 6.25 (1H, d), 7.10 (1H, d)

Reference Example 350 tert-butyl(3S,5R)-3-[{[1-(4-methoxybutyl)-5-phenyl-1H-pyrrol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

To a mixture of 1-(4-methoxybutyl)-5-phenyl-1H-pyrrole-2-carboxylic acid(137 mg), 1-tert-butyl3-methyl(3R,5S)-5-(isobutylamino)piperidine-1,3-dicarboxylate (134 mg),chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (168 mg)and 1,2-dichloroethane (5 ml) was added diisopropylethylamine (0.449 ml)and the mixture was stirred at room temperature for 12 hr. The reactionmixture was concentrated under reduced pressure, diluted with water, andpartitioned. The aqueous layer was extracted with ethyl acetate, theorganic layers were combined and dried over anhydrous sodium sulfate.The solvent was evaporated under reduced pressure. The residue wassubjected to silica gel column chromatography, and a fraction elutedwith ethyl acetate-hexane (1:1-1:0) was concentrated under reducedpressure to give the object product (150 mg).

MS (ESI+, m/e) 625 (M+1)

In the same manner as in Reference Example 350, the following compounds(Reference Examples 351-354) were synthesized.

Reference Example 351 tert-butyl(3S,5R)-3-[{[1-(4-methoxybutyl)-5-(1-methylethyl)-1H-pyrrol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 592 (M+1)

Reference Example 352 tert-butyl(3S,5R)-3-[{[1-(4-methoxybutyl)-5-(thiophen-2-yl)-1H-pyrrol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 631 (M+1)

Reference Example 353 tert-butyl(3S,5R)-3-[{[1-(4-methoxybutyl)-5-(2-methoxyphenyl)-1H-pyrrol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 655 (M+1)

Reference Example 354 tert-butyl(3S,5R)-3-[{[5-bromo-1-(4-methoxybutyl)-1H-pyrrol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 628 (M+1)

Reference Example 355 tert-butyl(3S,5R)-3-[{[1-(4-methoxybutyl)-5-(pyridin-3-yl)-1H-pyrrol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

A mixture of tert-butyl(3S,5R)-3-[{[5-bromo-1-(4-methoxybutyl)-1H-pyrrol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(188 mg), pyridin-3-ylboronic acid (41 mg),tetrakis(triphenylphosphine)palladium(0) (35 mg), sodium carbonate (371mg), ethanol (2 ml), toluene (2 ml) and water (2 ml) was heated underreflux for 12 hr. The reaction mixture was concentrated under reducedpressure, and the residue was suspended in ethyl acetate and washed withwater. The organic layer was dried over anhydrous sodium sulfate and thesolvent was evaporated under reduced pressure. The residue was subjectedto silica gel column chromatography, and a fraction eluted with ethylacetate-hexane (1:1-1:0) was concentrated under reduced pressure, andcrystals were collected by filtration to give the object product (200mg).

MS (ESI+, m/e) 626 (M+1)

Reference Example 356 tert-butyl(3S,5R)-3-[{[1-(4-methoxybutyl)-1H-pyrrol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

A mixture of tert-butyl(3S,5R)-3-[{[5-bromo-1-(4-methoxybutyl)-1H-pyrrol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(220 mg), pyridin-2-ylboronic acid (65 mg), sodium carbonate (370 mg),tetrakis(triphenylphosphine)palladium (40 mg), ethanol (2 ml), toluene(2 ml) and water (2 ml) was stirred at 80° C. for 12 hr. The solvent wasevaporated under reduced pressure. The residue was dissolved in ethylacetate-water, and the organic layer was washed with saturated brine,and dried over anhydrous sodium sulfate. The solvent was evaporatedunder reduced pressure. The residue was subjected to silica gel columnchromatography, and a fraction eluted with ethyl acetate-hexane(1:1-1:0) was concentrated under reduced pressure to give the objectproduct (240 mg).

MS (ESI+, m/e) 549 (M+1)

Example 1991-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-5-phenyl-1H-pyrrole-2-carboxamidehydrochloride

tert-Butyl(3S,5R)-3-[{[1-(4-methoxybutyl)-5-phenyl-1H-pyrrol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(150 mg) was dissolved in ethyl acetate (5 ml), 4N hydrogenchloride-ethyl acetate (5 ml) was added and the mixture was stirred for1 hr. The solvent was evaporated under reduced pressure to give theobject product (110 mg).

MS (ESI+, m/e) 525 (M+1)

In the same manner as in Example 199, the following compound wassynthesized.

Example 2001-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-5-(pyridin-3-yl)-1H-pyrrole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 526 (M+1)

Example 2011-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-5-(thiophen-2-yl)-1H-pyrrole-2-carboxamide

tert-Butyl(3S,5R)-3-[{[1-(4-methoxybutyl)-5-(thiophen-2-yl)-1H-pyrrol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(65 mg) was dissolved in ethyl acetate (2 ml), 4N hydrogenchloride-ethyl acetate (5 ml) was added and the mixture was stirred for1 hr. The solvent was evaporated under reduced pressure, and the residuewas subjected to reversed-phase preparative HPLC and the eluted fractionwas concentrated under reduced pressure. The residual aqueous layer wasneutralized with saturated aqueous sodium hydrogen carbonate andextracted with ethyl acetate. The extract was dried over anhydroussodium sulfate and the solvent was evaporated under reduced pressure togive the object product (20 mg).

MS (ESI+, m/e) 531 (M+1)

In the same manner as in Example 201, the following compound wassynthesized.

Example 2021-(4-methoxybutyl)-5-(2-methoxyphenyl)-N-(2-methylpropyl)-n-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-pyrrole-2-carboxamide

MS (ESI+, m/e) 531 (M+1)

Example 2031-(4-methoxybutyl)-5-(1-methylethyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-pyrrole-2-carboxamide

MS (ESI+, m/e) 492 (M+1)

Example 2041-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-pyrrole-2-carboxamide

MS (ESI+, m/e) 450 (M+1)

Example 205 Methyl 1-(4-methoxybutyl)-5-{(2-methylpropyl)[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]carbamoyl}-1H-pyrrole-2-carboxylate

5-(Methoxycarbonyl)-1H-pyrrole-2-carboxylic acid (160 mg), tert-butyl(3S,5R)-3-[(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(250 mg) obtained in Reference Example 22 and N,N-diisopropylethylamine(6301) were dissolved in 1,2-dichloroethane (10 ml),chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (410 mg)was added and the mixture was stirred at room temperature for 3 hr. Thereaction mixture was concentrated, diluted with aqueous calciumcarbonate solution and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The residue was subjected to silica gel column chromatography, and afraction eluted with ethyl acetate-hexane (0:10-10:0) was concentratedunder reduced pressure. The residue was dissolved in DMA (10 ml), cesiumcarbonate (790 mg) and 4-methoxybutyl methanesulfonate (230 mg) wereadded, and the mixture was stirred at 70° C. overnight. The reactionmixture was concentrated under reduced pressure, the residue was dilutedwith water, and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, and dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas dissolved in TFA (1.0 ml), and the mixture was stirred at roomtemperature for 30 min, and concentrated under reduced pressure. Thiswas purified by HPCL, and the object fraction was concentrated, theresidue was diluted with aqueous calcium carbonate solution and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure to give the object product (62.9mg).

MS (ESI+, m/e) 507 (M+1)

In the same manner as in the method shown in Example 7, the followingcompound (Example 206) was obtained.

Example 206(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl(3R,5S)-5-[{[5-(4-methoxybutyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylatehydrochloride

MS (ESI+, m/e) 570 (M+1)

In the same manner as in Reference Example 362, the following compound(Reference Example 357) was obtained.

Reference Example 357 methyl5-acetyl-1-(4-methoxybutyl)-1H-pyrrole-2-carboxylate

MS (ESI+, m/e) 254 (M+1)

¹H-NMR (CDCl₃) δ 1.57-1.82 (4H, m), 2.49 (3H, s), 3.32 (3H, s), 3.40(2H, t), 3.85 (3H, s), 4.84 (2H, t), 6.88 (2H, s).

In the same manner as in Reference Example 11, the following compound(Reference Example 358) was obtained.

Reference Example 3585-acetyl-1-(4-methoxybutyl)-1H-pyrrole-2-carboxylic acid

MS (ESI+, m/e) 240 (M+1)

¹H-NMR (CDCl₃) δ 1.58-1.68 (2H, m), 1.74-1.84 (2H, m), 2.52 (3H, s),3.34 (3H, s), 3.42 (2H, t), 4.85 (2H, t), 6.92 (1H, d), 7.04 (1H, d),8.66 (1H, br).

Reference Example 359 methyl 7-methoxy-3-oxoheptanoate

A solution of 5 methoxypentanoic acid (26.4 g) in THF (250 ml) wascooled 0° C.-5° C., and oxalyl chloride (50.8 g) was added dropwise over30 min. The mixture was stirred at room temperature for 2 hr. Thesolvent was concentrated under reduced pressure.

A solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (28.8 g) indichloromethane (300 ml) was cooled to 0° C.-5° C., pyridine (31.6 g)was added, and 5-methoxypentanoyl chloride/dichloromethane solution (20ml) was added dropwise over 30 min. The mixture was stirred at 0° C.-5°C. for 1 hr.

The reaction mixture was poured into 0.5N hydrochloric acid (300 ml),washed with water, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure. The residue was dissolvedin methanol (450 ml) and the mixture was stirred under reflux for 15 hr.The solvent was concentrated under reduced pressure, and the residue wasdistilled under reduced pressure. The fraction distilled under reducedpressure of 0.3 mmHg at 90° C.-92° C. was collected to give the objectproduct (27.4 g) as an oil.

MS (ESI+, m/e) 189 (M+1)

¹H-NMR (CDCl₃) δ 1.55-1.72 (4H, m), 2.57 (2H, t), 3.31 (3H, t), 3.37(3H, t), 3.45 (2H, s), 3.73 (3H, s).

Reference Example 3605-(4-methoxybutyl)-1-phenyl-1H-1,2,3-triazole-4-carboxylic acid

A solution of sodium hydride (60% in oil, 2 g) in DMF (50 ml) was cooledto 0° C.-5° C., methyl 7-methoxy-3-oxoheptanoate (9.4 g) was added, andthe mixture was stirred at 0° C.-5° C. for min. Phenyl azide (6 g) wasadded, and the mixture was stirred at room temperature for 15 hr. Thesolvent was concentrated under reduced pressure, and methanol (100 ml)was added to the residue and 4N aqueous sodium hydroxide solution (20ml) was further added. The mixture was stirred at 60° C. for 1 hr. Thesolvent was evaporated under reduced pressure and water (100 ml) wasadded to the residue. 6N Hydrochloric acid was added for neutralizationand the mixture was extracted with ethyl acetate (100 ml×2). The extractwas dried over anhydrous sodium sulfate and the solvent was evaporatedunder reduced pressure. The residue was subjected to silica gel columnchromatography, and a fraction eluted with ethyl acetate wasconcentrated under reduced pressure to give the object product (7.2 g)as a white powder.

MS (ESI+, m/e) 276 (M+1)

¹H-NMR (CDCl₃) δ 1.49-1.70 (4H, m), 3.04 (2H, t), 3.27 (3H, s), 3.31(2H, t), 7.44-7.49 (2H, m), 7.58-7.61 (3H, m), 8.76 (1H, br).

Reference Example 3615-(4-methoxybutyl)-1-(2-methylphenyl)-1H-1,2,3-triazole-4-carboxylicacid

A solution of sodium hydride (60% in oil, 280 mg) in DMF (10 ml) wascooled to 0° C.-5° C., methyl 7-methoxy-3-oxoheptanoate (1.32 g) wasadded, and the mixture was stirred at 0° C.-5° C. for 30 min. Then,1-azido-2-methylbenzene (932 mg) was added, and the mixture was stirredat room temperature for 15 hr. The solvent was concentrated underreduced pressure, methanol (10 ml) was added to the residue, and 4Naqueous sodium hydroxide solution (5 ml) was added and the mixture wasstirred at 60° C. for 1 hr. The solvent was evaporated under reducedpressure and water (20 ml) was added to the residue. 6N Hydrochloricacid was added for neutralization and the mixture was extracted withethyl acetate (20 ml×2). The extract was dried over anhydrous sodiumsulfate and the solvent was evaporated under reduced pressure. Theresidue was subjected to silica gel column chromatography, and afraction eluted with ethyl acetate was concentrated under reducedpressure to give the object product (930 mg) as an oil.

MS (ESI+, m/e) 290 (M+1)

¹H-NMR (CDCl₃) δ 1.48-1.62 (4H, m), 2.06 (3H, s), 2.88 (2H, t), 3.24(3H, s), 3.27 (2H, t), 7.24-7.28 (1H, m), 7.38-7.54 (3H, m), 8.61 (1H,br).

In the same manner as in Reference Example 361, the following compounds(Reference Examples 362-372) were obtained.

Reference Example 3625-(4-methoxybutyl)-1-(3-methylphenyl)-1H-1,2,3-triazole-4-carboxylicacid

MS (ESI+, m/e) 290 (M+1)

¹H-NMR (CDCl₃) δ 1.50-1.70 (4H, m), 2.47 (3H, s), 3.03 (2H, t), 3.27(3H, s), 3.31 (2H, t), 7.24 (2H, t), 7.40 (1H, d), 7.47 (1H, t), 9.69(1H, br).

Reference Example 3635-(4-methoxybutyl)-(4-methylphenyl)-1H-1,2,3-triazole-4-carboxylic acid

MS (ESI+, m/e) 290 (M+1)

¹H-NMR (CDCl₃) δ 1.49-1.69 (4H, m), 2.48 (3H, s), 3.02 (2H, t), 3.28(3H, s), 3.31 (2H, t), 7.36 (4H, q), 10.71 (1H, br).

Reference Example 3645-(4-methoxybutyl)-1-(2-methoxyphenyl)-1H-1,2,3-triazole-4-carboxylicacid

MS (ESI+, m/e) 306 (M+1)

¹H-NMR (CDCl₃) δ 1.43-1.63 (4H, m), 2.88 (2H, br s), 3.25 (3H, s), 3.27(2H, t), 3.80 (3H, s), 7.09-7.16 (2H, m), 7.35 (1H, dd), 7.56 (1H, dt),10.23 (1H, br).

Reference Example 3655-(4-methoxybutyl)-1-(3-methoxyphenyl)-1H-1,2,3-triazole-4-carboxylicacid

MS (ESI+, m/e) 306 (M+1)

¹H-NMR (CDCl₃) δ 1.51-1.71 (4H, m), 3.05 (2H, t), 3.28 (3H, s), 3.32(2H, t), 3.88 (3H, s), 6.98-7.03 (2H, m), 7.12 (1H, dd), 7.48 (1H, t),10.43 (1H, br).

Reference Example 3665-(4-methoxybutyl)-1-(4-methoxyphenyl)-1H-1,2,3-triazole-4-carboxylicacid

MS (ESI+, m/e) 306 (M+1)

¹H-NMR (CDCl₃) δ 1.52-1.66 (4H, m), 3.00 (2H, t), 3.28 (3H, s), 3.31(2H, t), 3.90 (3H, s), 7.07 (2H, d), 7.36 (2H, d), 9.85 (1H, br).

Reference Example 3671-(3-chlorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazole-4-carboxylicacid

MS (ESI+, m/e) 310 (M+1)

¹H-NMR (CDCl₃) δ 1.52-1.71 (4H, m), 3.06 (2H, t), 3.29 (3H, s), 3.34(2H, t), 7.37-7.43 (1H, m), 7.51-7.61 (3H, m), 9.31 (1H, br).

Reference Example 3681-(4-chlorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazole-4-carboxylicacid

MS (ESI+, m/e) 310 (M+1)

¹H-NMR (CDCl₃) δ 1.50-1.70 (4H, m), 3.03 (2H, t), 3.28 (3H, s), 3.32(2H, t), 7.42 (2H, d), 7.59 (2H, d), 7.83 (1H, br).

Reference Example 3691-(3-fluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazole-4-carboxylicacid

MS (ESI+, m/e) 294 (M+1)

¹H-NMR (CDCl₃) δ 1.52-1.72 (4H, m), 3.07 (2H, t), 3.29 (3H, s), 3.34(2H, t), 7.23-7.35 (3H, m), 7.56-7.63 (1H, m), 9.06 (1H, br).

Reference Example 3701-(4-fluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazole-4-carboxylicacid

MS (ESI+, m/e) 294 (M+1)

¹H-NMR (CDCl₃) δ 1.51-1.69 (4H, m), 3.02 (2H, t), 3.28 (3H, s), 3.33(2H, t), 7.26-7.32 (2H, m), 7.44-7.49 (2H, m), 10.15 (1H, br).

Reference Example 3715-(4-methoxybutyl)-1-[3-(trifluoromethyl)phenyl]-1H-1,2,3-triazole-4-carboxylicacid

MS (ESI+, m/e) 344 (M+1)

¹H-NMR (CDCl₃) δ 1.53-1.73 (4H, m), 3.07 (2H, t), 3.27 (3H, s), 3.33(2H, t), 7.70 (1H, d), 7.78 (2H, t), 7.89 (1H, d), 10.18 (1H, br).

Reference Example 3721-(3,4-difluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazole-4-carboxylicacid

MS (ESI+, m/e) 312 (M+1)

¹H-NMR (CDCl₃) δ 1.53-1.71 (4H, m), 3.05 (2H, t), 3.30 (3H, s), 3.35(2H, t), 7.25-7.30 (1H, m), 7.37-7.44 (2H, m), 9.61 (1H, br).

Reference Example 3731-(2-fluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazole-4-carboxylicacid

A solution of methyl 7-methoxy-3-oxoheptanoate (2.0 g) in methanol (70ml) was cooled to 0° C.-5° C., 1-azido-2-fluorobenzene (960 mg) and 28%sodium methoxide methanol solution (2 g) were added and the mixture wasstirred at 60° C. for 3 hr. Then, 1N sodium hydroxide (14 ml) was added,and the mixture was stirred at 60° C. for 1 hr. The solvent wasevaporated under reduced pressure and water (20 ml) was added to theresidue. 1N Hydrochloric acid was added for neutralization and themixture was extracted with ethyl acetate (50 ml×2). The extract wasdried over anhydrous sodium sulfate and the solvent was evaporated underreduced pressure. The residue was subjected to silica gel columnchromatography, and a fraction eluted with ethyl acetate wasconcentrated under reduced pressure to give the object product (1.61 g)as an oil.

MS (ESI+, m/e) 294 (M+1)

¹H-NMR (CDCl₃) δ 1.45-1.64 (4H, m), 2.97 (2H, t), 3.25 (3H, s), 3.29(2H, t), 7.33-7.41 (2H, m), 7.46-7.51 (1H, m), 7.59-7.66 (1H, m), 9.27(1H, br).

Reference Example 3741-(2-chlorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazole-4-carboxylicacid

A solution of methyl 7-methoxy-3-oxoheptanoate (2.0 g) in methanol (70ml) was cooled to 0° C.-5° C., 1-azido-2-chlorobenzene (1.08 g) and 28%sodium methoxide methanol solution (2 g) were added and the mixture wasstirred at 60° C. for 3 hr. Then, 1N sodium hydroxide (14 ml) was added,and the mixture was stirred at 60° C. for 1 hr. The solvent wasevaporated under reduced pressure and water (20 ml) was added to theresidue. 1N Hydrochloric acid was added for neutralization and themixture was extracted with ethyl acetate (50 ml×2). The extract wasdried over anhydrous sodium sulfate and the solvent was evaporated underreduced pressure. The residue was subjected to silica gel columnchromatography, and a fraction eluted with ethyl acetate wasconcentrated under reduced pressure to give the object product (1.26 g)as a powder.

MS (ESI+, m/e) 310 (M+1)

¹H-NMR (CDCl₃) δ 1.46-1.59 (4H, m), 2.92 (2H, t), 3.25 (3H, s), 3.29(2H, t), 7.44-7.67 (4H, m), 9.43 (1H, br).

In the same manner as in Reference Example 374, the following compounds(Reference Examples 375-377) were obtained.

Reference Example 3751-(2,3-difluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazole-4-carboxylicacid

MS (ESI+, m/e) 312 (M+1)

¹H-NMR (CDCl₃) δ 1.48-1.67 (4H, m), 3.00 (2H, t), 3.26 (3H, s), 3.31(2H, t), 7.28-7.40 (2H, m), 7.44-7.52 (1H, m), 8.88 (1H, br).

Reference Example 3761-(2,6-difluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazole-4-carboxylicacid

MS (ESI+, m/e) 312 (M+1)

¹H-NMR (CDCl₃) δ 1.48-1.67 (4H, m), 2.95 (2H, t), 3.26 (3H, s), 3.31(2H, t), 7.20 (2H, t), 7.57-7.67 (1H, m), 8.69 (1H, br).

Reference Example 3771-(3,5-difluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazole-4-carboxylicacid

MS (ESI+, m/e) 312 (M+1)

¹H-NMR (CDCl₃) δ 1.55-1.73 (4H, m), 3.10 (2H, t), 3.30 (3H, s), 3.36(2H, t), 7.05-7.15 (3H, m), 9.78 (1H, br).

Reference Example 3781-phenyl-5-(2-phenylethyl)-1H-1,2,3-triazole-4-carboxylic acid

A solution of ethyl 3-oxo-5-phenylpentanoate (1.1 g) in methanol (50 ml)was cooled to 0° C.-5° C., azidobenzene (600 mg) and 28% sodiummethoxide methanol solution (965 mg) were added and the mixture wasstirred at 60° C. for 3 hr. Then, 1N sodium hydroxide (10 ml) was addedand the mixture was stirred at 60° C. for 1 hr. The solvent wasevaporated under reduced pressure and water (20 ml) was added. 1NHydrochloric acid was added for neutralization and the mixture wasextracted with ethyl acetate (30 ml×2). The extract was dried overanhydrous sodium sulfate and the solvent was evaporated under reducedpressure. The residue was subjected to silica gel column chromatography,and a fraction eluted with ethyl acetate was concentrated under reducedpressure to give the object product (480 mg) as a powder.

MS (ESI+, m/e) 294 (M+1)

¹H-NMR (CDCl₃) δ 2.93 (2H, t), 3.31 (2H, t), 6.93-6.96 (2H, m),7.14-7.21 (5H, m), 7.48-7.60 (3H, m), 9.23 (1H, br).

Reference Example 379 tert-butyl(3S,5R)-3-[{[5-(4-methoxybutyl)-1-phenyl-TH-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

5-(4-Methoxybutyl)-1-phenyl-1H-1,2,3-triazole-4-carboxylic acid (138mg), tert-butyl(3S,5R)-3-[(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(185 mg) and N,N-diisopropylethylamine (345 μl) were dissolved in1,2-dichloroethane (5 ml), chloro-N,N,N′,N′-tetramethylformamidiniumhexafluorophosphate (154 mg) was added and the mixture was stirred atroom temperature for 15 hr. The reaction mixture was diluted withsaturated aqueous sodium hydrogen carbonate solution and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The residue was subjected to silicagel column chromatography, and a fraction eluted with ethylacetate-hexane (10:90-100:0) was concentrated under reduced pressure togive the object product (235 mg) as an amorphous compound.

MS (ESI+, m/e) 627 (M+1)

In the same manner as in Reference Example 379, the following compounds(Reference Examples 380-381) were obtained.

Reference Example 380 tert-butyl(3S,5R)-3-[{[5-acetyl-1-(4-methoxybutyl)-1H-pyrrol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 591 (M+1)

Reference Example 381 tert-butyl4-[{[5-(4-methoxybutyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]octahydroisoquinoline-2(1H)-carboxylate

MS (ESI+, m/e) 568 (M+1)

Reference Example 382 1-tert-butyl3-methyl(3R,5S)-5-[{[5-(4-methoxybutyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate

To a solution of5-(4-methoxybutyl)-1-phenyl-1H-1,2,3-triazole-4-carboxylic acid (2.75 g)in THF (50 ml) were added thionyl chloride (0.876 ml) and DMF (5 drops),and the mixture was heated under reflux with stirring for 2 hr. Thereaction mixture was cooled to room temperature, concentrated underreduced pressure, and the residue was azeotroped with toluene (25 ml).The obtained residue was dissolved in THF (10 ml), added to a solutionof 1-tert-butyl3-methyl(3R,5S)-5-[(2-methylpropyl)amino]piperidine-1,3-dicarboxylate(3.14 g) and diisopropylethylamine (5.2 g) in THF (50 ml) and themixture was stirred at room temperature for 2 hr. The reaction mixturewas concentrated under reduced pressure, diluted with water, andextracted with ethyl acetate (50 ml). The extract was washedsuccessively with 1M hydrochloric acid and saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The residue was subjected to silica gel columnchromatography, and a fraction eluted with ethyl acetate-hexane(5:95-50:50) was concentrated under reduced pressure to give the objectproduct (4.32 g).

MS (ESI+, m/e) 572 (M+1)

Reference Example 383 tert-butyl(3R,5S)-3-(1-hydroxy-1-methylethyl)-5-[{[5-(4-methoxybutyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate

A solution of 1-tert-butyl3-methyl(3R,5S)-5-[{[5-(4-methoxybutyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate(286 mg) in THF (5 ml) was cooled to −40° C. Methylmagnesium bromide(3M-diethyl ether solution, 1 ml) was added thereto and the mixture wasstirred at the same temperature for 30 min. Saturated aqueous ammoniumchloride solution was added to the reaction mixture, and the mixture wasextracted with ethyl acetate (10 ml×2). The extract was washed withsaturated brine, and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography [eluent: n-hexane-ethyl acetate(7:3→3:7)] to give the object product (180 mg) as an amorphous compound.

MS (ESI+, m/e) 572 (M+1)

Reference Example 384(3R,5S)-1-(tert-butoxycarbonyl)-5-[{[5-(4-methoxybutyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid

To a solution of 1-tert-butyl3-methyl(3R,5S)-5-[{[5-(4-methoxybutyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate(1.715 g) in methanol (10 ml) was added 4N aqueous sodium hydroxidesolution (10 ml), and the mixture was stirred at 65° C. for 30 min. Thesolvent was concentrated under reduced pressure, and the residue wasneutralized with 10% aqueous citric acid solution. The mixture wasextracted with ethyl acetate (20 ml×2) and the extract was dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure to give the object product (1.56 g) as an amorphous compound.

MS (ESI+, m/e) 558 (M+1)

Reference Example 385 tert-butyl(3S,5R)-3-[{[5-(4-methoxybutyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(pyrrolidin-1-ylcarbonyl)piperidine-1-carboxylate

A solution of(3R,5S)-1-(tert-butoxycarbonyl)-5-[{[5-(4-methoxybutyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid (279 mg), pyrrolidine (42 μl), WSC.HCl (144 mg), HOBt (107 mg),diisopropylethylamine (255 μl) and DMF (3 ml) was stirred at roomtemperature for 15 hr. The reaction mixture was poured into saturatedaqueous sodium hydrogen carbonate, and the liberated oil was extractedwith ethyl acetate (20 ml). The extract was washed successively withwater and saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wassubjected to silica gel column chromatography, and a fraction elutedwith ethyl acetate was concentrated under reduced pressure to give theobject product (245 mg) as an amorphous compound.

MS (ESI+, m/e) 611 (M+1)

In the same manner as in Reference Example 385, the following compounds(Reference Examples 386-387) were obtained.

Reference Example 386 tert-butyl(3S,5R)-3-[{[5-(4-methoxybutyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(piperidin-1-ylcarbonyl)piperidine-1-carboxylate

Reference Example 387 tert-butyl(3R,5S)-3-(7-azabicyclo[2.2.1]hept-7-ylcarbonyl)-5-[{[5-(4-methoxybutyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate

MS (ESI+, m/e) 637 (M+1)

Reference Example 388 tert-butyl(3S,5R)-3-[{[1-(2-chlorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

To a solution of1-(2-chlorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazole-4-carboxylicacid (155 mg) in THF (5 ml) were added thionyl chloride (0.11 ml) andDMF (1 drop), and the mixture was heated under reflux with stirring for2 hr. The reaction mixture was cooled to room temperature, concentratedunder reduced pressure, and the residue was azeotroped with toluene (5ml). The obtained residue was dissolved in THF (5 ml), added to asolution of tert-butyl(3S,5R)-3-[(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(185 mg) and diisopropylethylamine (0.345 ml) in THF (5 ml) and themixture was stirred at room temperature for 2 hr. The reaction mixturewas concentrated under reduced pressure, diluted with water, andextracted with ethyl acetate (10 ml). The extract was washedsuccessively with 1M hydrochloric acid and saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The residue was subjected to silica gel columnchromatography, and a fraction eluted with hexane-ethyl acetate(5:95-30:70) was concentrated under reduced pressure to give the objectproduct (280 mg).

¹H-NMR (CDCl₃) δ 0.83-1.00 (6H, m), 1.43 (9H, s), 1.49-1.55 (4H, m),1.90-2.16 (2H, m), 2.47 (1H, br.s), 2.76-2.97 (5H, m), 3.21-3.25 (6H,m), 3.36-3.44 (1H, m), 3.61-3.73 (8H, m), 4.23-4.28 (2H, m), 4.68 (1H,br.s), 7.42-7.65 (4H, m).

MS (ESI+, m/e) 662 (M+1)

Reference Example 389 tert-butyl(3S,5R)-3-[{[1-(2-fluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

To a solution of1-(2-fluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazole-4-carboxylicacid (1.61 g) in THF (20 ml) were added thionyl chloride (1.2 ml) andDMF (5 drops), and the mixture was heated under reflux with stirring for2 hr. The reaction mixture was cooled to room temperature, soconcentrated under reduced pressure, and the residue was azeotroped withtoluene (20 ml). The obtained residue was dissolved in THF (5 ml), addedto a solution of tert-butyl(3S,5R)-3-[(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(2.03 g) and diisopropylethylamine (3.9 ml) in THF (30 ml) and themixture was stirred at room temperature for 2 hr. The reaction mixturewas concentrated under reduced pressure, diluted with water, andextracted with ethyl acetate (50 ml). The extract was washedsuccessively with 1M hydrochloric acid and saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The residue was subjected to silica gel columnchromatography, and a fraction eluted with hexane-ethyl acetate(5:95-30:70) was concentrated under reduced pressure to give the objectproduct (2.64 g).

¹H-NMR (CDCl₃) δ 0.84-0.99 (6H, m), 1.41 (9H, s), 1.48-1.55 (4H, m),1.90-2.16 (2H, m), 2.44 (1H, br.s), 2.61-2.99 (5H, m), 3.20-3.28 (6H m),3.36-3.44 (1H, m), 3.61-3.76 (8H, m), 4.23 (2H, br.s), 4.66 (1H, br.s),7.31-7.39 (2H, m), 7.42-7.46 (1H, m), 7.56-7.63 (1H, m).

MS (ESI+, m/e) 645 (M+1)

In the same manner as in Reference Example 389, the following compounds(Reference Examples 390-399) were obtained.

Reference Example 390 tert-butyl(3S,5R)-3-[{[1-(3-chlorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 662 (M+1)

Reference Example 391 tert-butyl(3S,5R)-3-[({5-(4-methoxybutyl)-1-[3-(trifluoromethyl)phenyl]-1H-1,2,3-triazol-4-yl}carbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 695 (M+1)

Reference Example 392 tert-butyl(3S,5R)-3-[{[1-(4-fluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 645 (M+1)

Reference Example 393 tert-butyl(3S,5R)-3-[{[1-(4-chlorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 662 (M+1)

Reference Example 394 tert-butyl(3S,5R)-3-[{[1-(3-fluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 645 (M+1)

Reference Example 395 tert-butyl(3S,5R)-3-[{[1-(3,4-difluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 663 (M+1)

Reference Example 396 tert-butyl(3S,5R)-3-[{[1-(2,3-difluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 663 (M+1)

Reference Example 397 tert-butyl(3S,5R)-3-[{[1-(2,6-difluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 663 (M+1)

Reference Example 398 tert-butyl(3S,5R)-3-[{[1-(3,5-difluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 663 (M+1)

Reference Example 399 tert-butyl (3S,5R)-3-[(2-methylpropyl){[1-phenyl-5-(2-phenylethyl)-1H-1,2,3-triazol-4-yl]carbonyl}amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 645 (M+1)

Reference Example 400 1-tert-butyl3-methyl(3R,5S)-5-[{[5-(4-methoxybutyl)-1-(2-methylphenyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate

To a solution of5-(4-methoxybutyl)-1-(2-methylphenyl)-1H-1,2,3-triazole-4-carboxylicacid (930 mg) in THF (10 ml) were added thionyl chloride (0.7 ml) andDMF (1 drop), and the mixture was heated under reflux with stirring for2 hr. The reaction mixture was cooled to room temperature, concentratedunder reduced pressure, and the residue was azeotroped with toluene (5ml). The obtained residue was dissolved in THF (1=ml), added to asolution of 1-tert-butyl3-methyl(3R,5S)-5-[(2-methylpropyl)amino]piperidine-1,3-dicarboxylate(1.0 g) and diisopropylethylamine (2.2 ml) in THF (10 ml) and themixture was stirred at room temperature for 2 hr. The reaction mixturewas concentrated under reduced pressure, diluted with water, andextracted with ethyl acetate (20 ml). The extract was washedsuccessively with 1M hydrochloric acid and saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The residue was subjected to silica gel columnchromatography, and a fraction eluted with ethyl acetate-hexane(5:95-50:50) was concentrated under reduced pressure to give the objectproduct (1.47 g) as an oil.

MS (ESI+, m/e) 586 (M+1)

In the same manner as in Reference Example 400, the following compounds(Reference Examples 401-405) were obtained.

Reference Example 401 1-tert-butyl3-methyl(3R,5S)-5-[{[5-(4-methoxybutyl)-1-(3-methylphenyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate

MS (ESI+, m/e) 586 (M+1)

Reference Example 402 1-tert-butyl3-methyl(3R,5S)-5-[{[5-(4-methoxybutyl)-1-(4-methylphenyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate

MS (ESI+, m/e) 586 (M+1)

Reference Example 403 1-tert-butyl3-methyl(3R,5S)-5-[{[5-(4-methoxybutyl)-1-(2-methoxyphenyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate

MS (ESI+, m/e) 602 (M+1)

Reference Example 404 1-tert-butyl3-methyl(3R,5S)-5-[{[5-(4-methoxybutyl)-1-(3-methoxyphenyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate

MS (ESI+, m/e) 602 (M+1)

Reference Example 405 1-tert-butyl3-methyl(3R,5S)-5-[{[5-(4-methoxybutyl)-1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate

MS (ESI+, m/e) 602 (M+1)

Reference Example 406(3R,5S)-(tert-butoxycarbonyl)-5-[{[5-(4-methoxybutyl)-1-(2-methylphenyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid

To a solution of 1-tert-butyl3-methyl(3R,5S)-5-[{[5-(4-methoxybutyl)-1-(2-methylphenyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-,3-dicarboxylate (1.47 g) in methanol (10 ml) was added 4N aqueous sodiumhydroxide solution (5 ml), and the mixture was stirred at 50° C. for 30min. The solvent was concentrated under reduced pressure, and theresidue was neutralized with 10% aqueous citric acid solution, extractedwith ethyl acetate (30 ml×2) and the extract was dried over anhydroussodium sulfate. The solvent was evaporated under reduced pressure togive the object product (1.3 g) as an amorphous compound.

MS (ESI+, m/e) 572 (M+1)

In the same manner as in Reference Example 406, the following compounds(Reference Examples 407-411) were obtained.

Reference Example 407(3R,5S)-1-(tert-butoxycarbonyl)-5-[{[5-(4-methoxybutyl)-(3-methylphenyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid

MS (ESI+, m/e) 572 (M+1)

Reference Example 408(3R,5S)-1-(tert-butoxycarbonyl)-5-[{[5-(4-methoxybutyl)-(4-methylphenyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid

MS (ESI+, m/e) 572 (M+1)

Reference Example 409(3R,5S)-1-(tert-butoxycarbonyl)-5-[{[5-(4-methoxybutyl)-1-(2-methoxyphenyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid

MS (ESI+, m/e) 588 (M+1)

Reference Example 410(3R,5S)-1-(tert-butoxycarbonyl)-5-[{[5-(4-methoxybutyl)-1-(3-methoxyphenyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid

MS (ESI+, m/e) 588 (M+1)

Reference Example 411(3R,5S)-(tert-butoxycarbonyl)-5-[{[5-(4-methoxybutyl)-1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid

Reference Example 412 tert-butyl(3S,5R)-3-[{[5-(4-methoxybutyl)-1-(2-methylphenyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

A solution of(3R,5S)-1-(tert-butoxycarbonyl)-5-[{[5-(4-methoxybutyl)-1-(2-methylphenyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid (286 mg), morpholine (44 μl), WSC.HCl (144 mg), HOBt (107 mg),diisopropylethylamine (255 μl) and DMF (3 ml) was stirred at roomtemperature for 15 hr. The reaction mixture was poured into saturatedaqueous sodium hydrogen carbonate, and the liberated oil was extractedwith ethyl acetate (20 ml). The extract was washed successively withwater and saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wassubjected to silica gel column chromatography, and a fraction elutedwith ethyl acetate was concentrated under reduced pressure to give theobject product (255 mg) as an amorphous compound.

MS (ESI+, m/e) 641 (M+1)

In the same manner as in Reference Example 412, the following compounds(Reference Examples 413-417) were obtained.

Reference Example 413 tert-butyl(3S,5R)-3-[{[5-(4-methoxybutyl)-1-(3-methylphenyl)-1H-1,2,3-triazol-4-yl]carbonyl}(3-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 641 (M+1)

Reference Example 414 tert-butyl(3S,5R)-3-[{[5-(4-methoxybutyl)-1-(4-methylphenyl)-1H-1,2,3-triazol-4-yl]carbonyl}(4-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 641 (M+1)

Reference Example 415 tert-butyl(3S,5R)-3-[{[5-(4-methoxybutyl)-1-(2-methoxyphenyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 657 (M+1)

Reference Example 416 tert-butyl(3S,5R)-3-[{[5-(4-methoxybutyl)-1-(3-methoxyphenyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 657 (M+1)

Reference Example 417 tert-butyl(3S,5R)-3-{[5-(4-methoxybutyl)-1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 657 (M+1)

Reference Example 418 1-tert-butyl3-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl](3R,5S)-5-[{[5-(4-methoxybutyl)-1-(2-methylphenyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate

To a solution of(3R,5S)-1-(tert-butoxycarbonyl)-5-[{[5-(4-methoxybutyl)-(2-methylphenyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid (286 mg) and 4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one (78 mg) inDMA (5 ml) were added toluenesulfonyl chloride (64 mg), DMAP (12 mg) andpotassium carbonate (90 mg) under ice-cooling, and the mixture wasstirred at 0° C. for 6 hr and at room temperature for 15 hr. Thereaction mixture was poured into ice-cooled 5% aqueous citric acid (10ml), and the liberated oil was extracted with ethyl acetate (20 ml). Theextract was washed with brine, and dried over anhydrous sodium sulfate.The solvent was evaporated under reduced pressure. The residue wassubjected to silica gel column chromatography, and a fraction elutedwith hexane-ethyl acetate (50:50) was concentrated under reducedpressure to give the object product (210 mg) as an amorphous compound.

MS (ESI+, m/e) 684 (M+1)

In the same manner as in Example 2, the following compounds (Examples207-230) were obtained.

Example 2075-acetyl-1-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-pyrrole-2-carboxamidehydrochloride

MS (ESI+, m/e) 517 (M+1)

Example 208N-(decahydroisoquinolin-4-yl)-5-(4-methoxybutyl)-N-(2-methylpropyl)-1-phenyl-1H-1,2,3-triazole-4-carboxamidehydrochloride

MS (ESI+, m/e) 468 (M+1)

Example 209methyl(3R,5S)-5-[{[5-(4-methoxybutyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylatehydrochloride

MS (ESI+, m/e) 472 (M+1)

Example 210N-[(3S,5R)-5-(1-hydroxy-1-methylethyl)piperidin-3-yl]-5-(4-methoxybutyl)-N-(2-methylpropyl)-1-phenyl-1H-1,2,3-triazole-4-carboxamidehydrochloride

MS (ESI+, m/e) 472 (M+1)

Example 2115-(4-methoxybutyl)-N-(2-methylpropyl)-1-phenyl-N-[(3S,5R)-5-(piperidin-1-ylcarbonyl)piperidin-3-yl]-1H-1,2,3-triazole-4-carboxamidehydrochloride

MS (ESI+, m/e) 525 (M+1)

Example 212N-[(3S,5R)-5-(7-azabicyclo[2.2.1]hept-7-ylcarbonyl)piperidin-3-yl]-5-(4-methoxybutyl)-N-(2-methylpropyl)-1-phenyl-1H-1,2,3-triazole-4-carboxamidehydrochloride

MS (ESI+, m/e) 537 (M+1)

Example 2131-(3-chlorophenyl)-5-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-1,2,3-triazole-4-carboxamidehydrochloride

MS (ESI+, m/e) 562 (M+1)

Example 2145-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1-[3-(trifluoromethyl)phenyl]-1H-1,2,3-triazole-4-carboxamidehydrochloride

MS (ESI+, m/e) 595 (M+1)

Example 2151-(4-fluorophenyl)-5-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-1,2,3-triazole-4-carboxamidehydrochloride

MS (ESI+, m/e) 595 (M+1)

Example 2161-(4-chlorophenyl)-5-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-1,2,3-triazole-4-carboxamidehydrochloride

MS (ESI+, m/e) 562 (M+1)

Example 2171-(3-fluorophenyl)-5-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-1,2,3-triazole-4-carboxamidehydrochloride

MS (ESI+, m/e) 545 (M+1)

Example 2181-(3,4-difluorophenyl)-5-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-1,2,3-triazole-4-carboxamidehydrochloride

MS (ESI+, m/e) 563 (M+1)

Example 219(3R,5S)-5-[{[5-(4-methoxybutyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid hydrochloride

MS (ESI+, m/e) 458 (M+1)

Example 2205-(4-methoxybutyl)-1-(3-methylphenyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-1,2,3-triazole-4-carboxamidehydrochloride

MS (ESI+, m/e) 541 (M+1)

Example 2215-(4-methoxybutyl)-1-(4-methylphenyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-1,2,3-triazole-4-carboxamidehydrochloride

MS (ESI+, m/e) 541 (M+1)

Example 2225-(4-methoxybutyl)-1-(2-methoxyphenyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-1,2,3-triazole-4-carboxamidehydrochloride

MS (ESI+, m/e) 557 (M+1)

Example 2235-(4-methoxybutyl)-1-(3-methoxyphenyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-1,2,3-triazole-4-carboxamidehydrochloride

MS (ESI+, m/e) 557 (M+1)

Example 2245-(4-methoxybutyl)-1-(4-methoxyphenyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-1,2,3-triazole-4-carboxamidehydrochloride

MS (ESI+, m/e) 557 (M+1)

Example 2251-(2,3-difluorophenyl)-5-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-1,2,3-triazole-4-carboxamidehydrochloride

MS (ESI+, m/e) 563 (M+1)

Example 2261-(2,6-difluorophenyl)-5-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-1,2,3-triazole-4-carboxamidehydrochloride

MS (ESI+, m/e) 563 (M+1)

Example 2271-(3,5-difluorophenyl)-5-(4-methoxybutyl)-N-(2-methypropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-1,2,3-triazole-4-carboxamidehydrochloride

MS (ESI+, m/e) 563 (M+1)

Example 228N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1-phenyl-5-(2-phenylethyl)-1H-1,2,3-triazole-4-carboxamidehydrochloride

MS (ESI+, m/e) 545 (M+1)

Example 229(3R,5S)-5-[{[5-(4-methoxybutyl)-(2-methylphenyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid hydrochloride

MS (ESI+, m/e) 472 (M+1)

Example 230(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl(3R,5S)-5-[{[5-(4-methoxybutyl)-1-(2-methylphenyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylatehydrochloride

MS (ESI+, m/e) 584 (M+1)

Example 2315-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1-phenyl-1H-1,2,3-triazole-4-carboxamidehydrochloride

tert-Butyl(3S,5R)-3-[{[5-(4-methoxybutyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(235 mg) was dissolved in ethyl acetate (0.5 ml), 4N hydrogenchloride-ethyl acetate solution (0.5 ml) was added, and the mixture wasstirred at room temperature for 1 hr. The solvent was evaporated underreduced pressure, and the residue was dried under reduced pressure togive the object product (200 mg).

MS (ESI+, m/e) 527 (M+1)

¹H-NMR (DMSO-d₆) δ 0.80-0.85 (3H, m), 0.90-0.95 (3H, m), 1.36 (4H, brs), 1.98-2.48 (3H, m), 2.79-3.08 (1H, t), 3.10 (3H, s), 3.10-3.15 (2H,m), 3.24-3.37 (6H, m), 3.52-3.62 (8H, m), 4.19-4.66 (1H, m), 7.61-7.66(5H, m), 9.69 (2H, br s).

Example 2325-(4-methoxybutyl)-N-(2-methylpropyl)-1-phenyl-N-[(3S,5R)-5-(pyrrolidin-1-ylcarbonyl)piperidin-3-yl]-1H-1,2,3-triazole-4-carboxamidehydrochloride

tert-Butyl(3S,5R)-3-[{[5-(4-methoxybutyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(pyrrolidin-1-ylcarbonyl)piperidine-1-carboxylate(245 mg) was dissolved in ethyl acetate (0.5 ml), 4N hydrogenchloride-ethyl acetate solution (0.5 ml) was added, and the mixture wasstirred at room temperature for 1 hr. The solvent was evaporated underreduced pressure, and the residue was dried under reduced pressure togive the object product (205 mg).

MS (ESI+, m/e) 527 (M+1)

¹H-NMR (DMSO-d₆) δ 0.80-0.85 (3H, m), 0.90-0.95 (3H, m), 1.36 (4H, brs), 1.76-1.82 (2H, m), 1.87-1.98 (4H, m), 2.02-2.13 (2H, m), 2.79-2.84(2H, m), 2.90-2.97 (1H, m), 3.10 (3H, s), 3.13 (2H, t), 3.27-3.34 (6H,m), 3.47-3.66 (3H, m), 4.20-4.63 (1H, m), 7.61-7.66 (5H, m), 9.69 (2H,br s).

Example 2331-(2-fluorophenyl)-5-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-1,2,3-triazole-4-carboxamidehydrochloride

tert-Butyl(3S,5R)-3-[{[1-(2-fluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(85 mg) was dissolved in ethyl acetate (0.5 ml), 4N hydrogenchloride-ethyl acetate solution (0.5 ml) was added, and the mixture wasstirred at room temperature for 1 hr. The solvent was evaporated underreduced pressure, and the residue was dried under reduced pressure togive the object product (70 mg).

MS (ESI+, m/e) 545 (M+1)

¹H-NMR (DMSO-d₆) δ 0.78-0.85 (3H, m), 0.90-0.95 (3H, m), 1.36 (4H, brs), 1.99-2.46 (3H, m), 2.71 (2H, br s), 2.95 (1H, t), 3.09-3.13 (5H, m),3.23-3.33 (6H, m), 3.51-3.65 (8H, m), 4.20-4.63 (1H, m), 7.51 (1H, t),7.63 (1H, t), 7.73-7.87 (2H, m), 9.62 (2H, br s).

Example 2345-(4-methoxybutyl)-1-(2-methylphenyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-1,2,3-triazole-4-carboxamidehydrochloride

tert-Butyl(3S,5R)-3-[{[5-(4-methoxybutyl)-1-(2-methylphenyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(255 mg) was dissolved in ethyl acetate (0.5 ml), 4N hydrogenchloride-ethyl acetate solution (0.5 ml) was added, and the mixture wasstirred at room temperature for 1 hr. The solvent was evaporated underreduced pressure, and the residue was dried under reduced pressure togive the object product (220 mg).

MS (ESI+, m/e) 541 (M+1)

¹H-NMR (DMSO-d₆) δ 0.79-0.85 (3H, m), 0.90-0.95 (3H, m), 1.33 (4H, brs), 1.93-2.14 (6H, m), 2.62 (2H, br s), 2.88-3.03 (1H, m), 3.08-3.12(5H, m), 3.22-3.45 (6H, m), 3.50-3.67 (8H, m), 4.22-4.66 (1H, m),7.44-7.58 (4H, m), 9.76 (2H, br s).

Example 2351-(2-chlorophenyl)-5-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-1,2,3-triazole-4-carboxamidehydrochloride

tert-Butyl(3S,5R)-3-[{[1-(2-chlorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(280 mg) was dissolved in ethyl acetate (0.5 ml), 4N hydrogenchloride-ethyl acetate solution (0.5 ml) was added, and the mixture wasstirred at room temperature for 1 hr. The solvent was evaporated underreduced pressure, and the residue was dried under reduced pressure togive the object product (245 mg).

MS (ESI+, m/e) 562 (M+1)

¹H-NMR (DMSO-d₆) δ 0.82-0.85 (3H, m), 0.90-0.97 (3H, m), 1.41 (4H, brs), 1.98-2.17 (3H, m), 2.68 (2H, br s), 2.95-3.07 (1H, m), 3.13 (3H, s),3.16 (2H, t), 3.27-3.43 (6H, m), 3.55-3.64 (8H, m), 4.28-4.71 (1H, m),7.69 (1H, t), 7.75-7.82 (2H, m), 7.87 (1H, d), 9.67 (2H, br s).

In the same manner as in the method shown in Reference Example 149, thefollowing compound (Reference Example 419) was obtained.

Reference Example 419 tert-butyl(3S,5R)-3-[{[5-(4-methoxybutyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate

MS (ESI+, m/e) 601 (M+1)

Reference Example 420 tert-butyl(3R,5S)-3-amino-5-[{[5-(4-methoxybutyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate

(3R,5S)-1-(tert-Butoxycarbonyl)-5-[{[5-(4-methoxybutyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid (250 mg) was dissolved in toluene (5 ml), diphenylphosphoryl azide(0.15 ml) and triethylamine (94 μl) were added and the mixture wasstirred at 100° C. for 2 hr. The reaction mixture was cooled to roomtemperature, 8M aqueous sodium hydroxide solution (0.56 ml) was addedand the mixture was stirred at room temperature for 1 hr. The reactionmixture was diluted with saturated aqueous sodium hydrogen carbonate andthe mixture was extracted twice with ethyl acetate. The extract wasdried over anhydrous sodium sulfate and the solvent was evaporated underreduced pressure. The residue was subjected to basic silica gel columnchromatography, and a fraction eluted with ethyl acetate-hexane(1:1-1:0) and ethyl acetate-methanol (10:1) was concentrated underreduced pressure to give the object product (155 mg).

MS (ESI+, m/e) 529 (M+1)

Example 2365-(4-methoxybutyl)-N-[(3S,5R)-5-(5-methyl-1,3,4-oxadiazol-2-yl)piperidin-3-yl]-N-(2-methylpropyl)-1-phenyl-1H-1,2,3-triazole-4-carboxamide0.5 fumarate

(3R,5S)-1-(tert-Butoxycarbonyl)-5-[{[5-(4-methoxybutyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid (200 mg) was dissolved in toluene (5 ml), 5-methyl-1H-tetrazole (36mg) and N,N′-dicyclohexylcarbodiimide (96 mg) were added and the mixturewas stirred at 80° C. for 15 hr. Water was added to the reactionmixture, and the mixture was extracted with ethyl acetate. The extractwas washed with saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure. The residuewas subjected to silica gel column chromatography, and a fraction elutedwith ethyl acetate-hexane (1:3-1:1) was concentrated under reducedpressure. The residue was dissolved in toluene (1 ml), trifluoroaceticacid (1 ml) was added and the mixture was stirred at room temperaturefor 1 hr. The reaction mixture was concentrated under reduced pressure,basified with saturated aqueous sodium hydrogen carbonate, and themixture was extracted twice with ethyl acetate. The extract was driedover anhydrous sodium sulfate and the solvent was evaporated underreduced pressure. The residue was dissolved in methanol (1 ml), fumaricacid (12 mg) was added and the mixture was concentrated under reducedpressure to give the object product (85 mg).

MS (ESI+, m/e) 496 (M+1)

Reference Example 421 tert-butyl(3R,5S)-3-acetyl-5-[{[5-(4-methoxybutyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate

tert-Butyl(3S,5R)-3-[{[5-(4-methoxybutyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate(230 mg) was dissolved in THF (5 ml), a 1M solution (1.9 ml) ofmethylmagnesium bromide in THF was added at 0° C., and the mixture wasstirred at room temperature for 2 hr. Saturated aqueous ammoniumchloride solution was added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The extract was washed with water andsaturated brine, and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure. The residue was subjected tosilica gel column chromatography, and a fraction eluted with ethylacetate-hexane (1:5-1:2) was concentrated under reduced pressure to givethe object product (177 mg).

MS (ESI+, m/e) 556 (M+1)

In the same manner as in the method shown in Example 60, the followingcompound (Example 237) was obtained.

Example 237N-[(3S,5R)-5-acetylpiperidin-3-yl]-5-(4-methoxybutyl)-N-(2-methylpropyl)-[1-phenyl-1H-1,2,3-triazole-4-carboxamidehydrochloride

MS (ESI+, m/e) 456 (M+1)

Reference Example 422

tert-butyl(3′R,5′S)-5′-[{[5-(4-methoxybutyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-2-oxo-1,3′-bipiperidine-1′-carboxylate

tert-Butyl(3R,5S)-3-amino-5-[{[5-(4-methoxybutyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate(150 mg) was dissolved in THF (3 ml), diisopropylethylamine (74 μl) and5-bromovaleryl chloride (42 μl) were added at 0° C. and the mixture wasstirred at 0° C. for 1 hr. The reaction mixture was diluted with water,and the mixture was extracted with ethyl acetate. The extract was washedwith saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was dissolved in THF(10 ml), potassium tert-butoxide (96 mg) was added at 0° C. and themixture was stirred at room temperature for 1 hr. The reaction mixturewas concentrated under reduced pressure, the residue was diluted withwater, and the mixture was extracted with ethyl acetate. The extract waswashed with saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The obtained residue was subjectedto silica gel chromatography, and a fraction eluted with ethylacetate-hexane (1:3-1:0) was concentrated under reduced pressure to givethe object product (150 mg).

MS (ESI+, m/e) 611 (M+1)

In the same manner as in the method shown in Reference Example 422, thefollowing compounds (Reference Examples 423-424) were obtained.

Reference Example 423 tert-butyl(3S,5R)-3-[{[5-(4-methoxybutyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(2-oxopyrrolidin-1-yl)piperidine-1-carboxylate

MS (ESI+, m/e) 597 (M+1)

Reference Example 424 tert-butyl(3S,5R)-3-[{[5-(4-methoxybutyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(2-oxotetrahydropyrimidin-1(2H)-yl)piperidine-1-carboxylate

MS (ESI+, m/e) 612 (M+1)

In the same manner as in Example 60, the following compounds (Examples238-240) were obtained.

Example 238 5-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3′R,5′S)-2-oxo-1,3′-bipiperidin-5′-yl]-1-phenyl-1H-1,2,3-triazole-4-carboxamidehydrochloride

MS (ESI+, m/e) 511 (M+1)

Example 2395-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(2-oxopyrrolidin-1-yl)piperidin-3-yl]-1-phenyl-1H-1,2,3-triazole-4-carboxamidehydrochloride

MS (ESI+, m/e) 497 (M+1)

Example 2405-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(2-oxotetrahydropyrimidin-1(2H)-yl)piperidin-3-yl]-phenyl-1H-1,2,3-triazole-4-carboxamidehydrochloride

MS (ESI+, m/e) 512 (M+1)

Reference Example 425 methyl5-(4-methoxybutyl)-1-phenyl-1H-pyrazole-4-carboxylate

A solution of methyl 7-methoxy-3-oxoheptanoate (526 mg) andN,N-dimethylformamide dimethylacetal (0.45 ml) in toluene (5 ml) wasstirred at 80° C. for 5 hr. The reaction mixture was concentrated underreduced pressure, and the residue was dissolved in ethanol (5 ml).Phenylhydrazine (0.41 ml) was added and the mixture was stirred at 80°C. for 15 hr. The reaction mixture was concentrated under reducedpressure, water was added to the residue, and the mixture was extractedwith ethyl acetate. The extract was washed with saturated brine, anddried over anhydrous magnesium sulfate and concentrated under reducedpressure. The obtained residue was subjected to silica gelchromatography, and a fraction eluted with hexane-ethyl acetate-hexane(1:9-1:3) was concentrated under reduced pressure to give the objectproduct (620 mg) as an oil.

MS (ESI+, m/e) 289 (M+1)

In the same manner as in Reference Example 74, the following compound(Reference Example 426) was obtained.

Reference Example 4265-(4-methoxybutyl)-1-phenyl-1H-pyrazole-4-carboxylic acid

MS (ESI+, m/e) 275 (M+1)

In the same manner as in Reference Example 163, the following compounds(Reference Examples 427-428) were obtained.

Reference Example 427 tert-butyl(3S,5R)-3-[{[5-(4-methoxybutyl)-1-phenyl-1H-pyrazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 626 (M+1)

Reference Example 428 tert-butyl(3S)-3-[{[5-(4-methoxybutyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate

MS (ESI+, m/e) 514 (M+1)

In the same manner as in Example 60, the following compounds (Examples241-242) were obtained.

Example 2415-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1-phenyl-1H-pyrazole-4-carboxamidedihydrochloride

MS (ESI+, m/e) 526 (M+1)

Example 2425-(4-methoxybutyl)-N-(2-methylpropyl)-phenyl-N-[(3S)-piperidin-3-yl]-1H-1,2,3-triazole-4-carboxamidehydrochloride

MS (ESI+, m/e) 414 (M+1)

In the same manner as in Reference Examples 360 and 361, the followingcompounds (Reference Examples 429-430) were obtained.

Reference Example 4291-(2,3-dihydro-1H-inden-5-yl)-5-(4-methoxybutyl)-1H-1,2,3-triazole-4-carboxylicacid

MS (ESI+, m/e) 316 (M+1)

Reference Example 4301-(4-fluoro-3-methylphenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazole-4-carboxylicacid

MS (ESI+, m/e) 308 (M+1)

In the same manner as in Reference Example 163, the following compounds(Reference Examples 431-432) were obtained.

Reference Example 431 1-tert-butyl3-methyl(3R,5S)-5-[{[1-(2,3-dihydro-1H-inden-5-yl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate

MS (ESI+, m/e) 612 (M+1)

Reference Example 432 1-tert-butyl3-methyl(3R,5S)-5-[{[1-(4-fluoro-3-methylphenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate

MS (ESI+, m/e) 604 (M+1)

In the same manner as in Reference Example 74, the following compounds(Reference Examples 433-434) were obtained.

Reference Example 433(3R,5S)-1-(tert-butoxycarbonyl)-5-[{[1-(2,3-dihydro-1H-inden-5-yl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid

MS (ESI+, m/e) 598 (M+1)

Reference Example 434(3R,5S)-(tert-butoxycarbonyl)-5-[{[1-(4-fluoro-3-methylphenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid

MS (ESI+, m/e) 590 (M+1)

In the same manner as in Reference Example 385, the following compounds(Reference Examples 435-436) were obtained.

Reference Example 435 tert-butyl(3S,5R)-3-[{[1-(2,3-dihydro-1H-inden-5-yl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 667 (M+1)

Reference Example 436 tert-butyl(3S,5R)-3-[{[1-(4-fluoro-3-methylphenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 659 (M+1)

In the same manner as in Reference Example 80, the following compounds(Reference Examples 437-438) were obtained.

Reference Example 437 tert-butyl(3R,5S)-3-carbamoyl-5-[{[1-(2,3-dihydro-1H-inden-5-yl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate

MS (ESI+, m/e) 597 (M+1)

Reference Example 438 tert-butyl(3R,5S)-3-carbamoyl-5-[{[1-(4-fluoro-3-methylphenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate

MS (ESI+, m/e) 589 (M+1)

In the same manner as in Example 60, the following compounds (Examples243-246) were obtained.

Example 2431-(2,3-dihydro-1H-inden-5-yl)-5-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-1,2,3-triazole-4-carboxamidehydrochloride

MS (ESI+, m/e) 567 (M+1)

Example 2441-(4-fluoro-3-methylphenyl)-5-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-1,2,3-triazole-4-carboxamidehydrochloride

MS (ESI+, m/e) 559 (M+1)

Example 245(3R,5S)-5-[{[1-(2,3-dihydro-1H-inden-5-yl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxamidehydrochloride

MS (ESI+, m/e) 497 (M+1)

Example 246(3R,5S)-5-[{[1-(4-fluoro-3-methylphenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxamidehydrochloride

MS (ESI+, m/e) 489 (M+1)

In the same manner as in Reference Examples 360 and 361, the followingcompound (Reference Example 439) was obtained.

Reference Example 4391-(2,3-dihydro-1H-inden-4-yl)-5-(4-methoxybutyl)-1H-1,2,3-triazole-4-carboxylicacid

MS (ESI+, m/e) 316 (M+1)

In the same manner as in Reference Example 163, the following compound(Reference Example 440) was obtained.

Reference Example 440 1-tert-butyl3-methyl(3R,5S)-5-[{[1-(2,3-dihydro-1H-inden-4-yl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate

MS (ESI+, m/e) 612 (M+1)

In the same manner as in Reference Example 74, the following compound(Reference Example 441) was obtained.

Reference Example 441(3R,5S)-1-(tert-butoxycarbonyl)-5-[{[1-(2,3-dihydro-1H-inden-4-yl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylicacid

MS (ESI+, m/e) 597 (M+1)

In the same manner as in Reference Example 385, the following compound(Reference Example 442) was obtained.

Reference Example 442 tert-butyl(3S,5R)-3-[{[1-(2,3-dihydro-1H-inden-4-yl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 667 (M+1)

In the same manner as in Example 60, the following compound (Example247) was obtained.

Example 2471-(2,3-dihydro-1H-inden-4-yl)-5-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-1,2,3-triazole-4-carboxamidehydrochloride

MS (ESI+, m/e) 567 (M+1)

In the same manner as in Reference Example 385, the following compounds(Reference Examples 443-444) were obtained.

Reference Example 443 tert-butyl(3S,5R)-3-[{5-(4-methoxybutyl)-1-(2-methylphenyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(pyrrolidin-1-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 625 (M+1)

Reference Example 444 tert-butyl(3S,5R)-3-[{[5-(4-methoxybutyl)-1-(4-methylphenyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(pyrrolidin-1-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 625 (M+1)

In the same manner as in Example 60, the following compounds (Examples248-249) were obtained.

Example 2485-(4-methoxybutyl)-1-(2-methylphenyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(pyrrolidin-1-ylcarbonyl)piperidin-3-yl]-1H-1,2,3-triazole-4-carboxamidehydrochloride

MS (ESI+, m/e) 525 (M+1)

Example 2495-(4-methoxybutyl)-1-(4-methylphenyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(pyrrolidin-1-ylcarbonyl)piperidin-3-yl]-1H-1,2,3-triazole-4-carboxamidehydrochloride

MS (ESI+, m/e) 525 (M+1)

Reference Example 445 ethyl [(4-methoxybutyl)amino](thioxo)acetate

To a solution of 4-methoxybutane-1-amine hydrochloride (1.40 g) andtriethylamine (4.18 ml) in DMA (100 ml) was added dropwise ethylchloroglyoxylate (1.12 ml) at 0° C. The reaction mixture was stirred atroom temperature for 2 hr. Water was added to the reaction mixture, andthe mixture was extracted with ethyl acetate. The extract was washedsuccessively with 1M hydrochloric acid, aqueous sodium bicarbonate andsaturated brine, and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure. The residue was dissolved intoluene (100 ml), Lawesson's reagent (6.07 g) was added, and the mixturewas stirred at 90° C. for 2 hr. The reaction mixture was cooled to roomtemperature, aqueous sodium bicarbonate was added, and the mixture wasstirred for min and extracted with ethyl acetate. The extract was washedwith saturated brine, dried over anhydrous sodium sulfate, and subjectedto basic silica gel column chromatography. The fraction eluted withethyl acetate was concentrated under reduced pressure to give the objectproduct (1.2 g).

MS (ESI+, m/e) 220 (M+1)

Reference Example 446 butyl4-(4-methoxybutyl)-5-phenyl-4H-1,2,4-triazole-3-carboxylate

Ethyl [(4-methoxybutyl)amino](thioxo)acetate (1.2 g) and benzohydrazide(745 mg) were dissolved in 1-butanol (10 ml), and the mixture wasstirred at 140° C. for 15 hr. The reaction mixture was cooled to roomtemperature, 10% aqueous citric acid solution was added, and the mixturewas extracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. The residue was subjected to silicagel column chromatography, and a fraction eluted with ethylacetate-hexane (8:2) was concentrated under reduced pressure to give theobject product (80 mg).

MS (ESI+, m/e) 332 (M+1)

In the same manner as in the method shown in Reference Example 54, thefollowing compound (Reference Example 447) was obtained.

Reference Example 447 tert-butyl(3S,5R)-3-[{[4-(4-methoxybutyl)-5-phenyl-4H-1,2,4-triazol-3-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 627 (M+1)

In the same manner as in the method shown in Example 11, the followingcompound (Example 250) was obtained.

Example 2504-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-5-phenyl-4H-1,2,4-triazole-3-carboxamidehydrochloride

MS (ESI+, m/e) 527 (M+1)

In the same manner as in Example 121, the following compound (Example251) was obtained.

Example 251N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1-phenyl-5-propyl-1H-pyrazole-4-carboxamidetrifluoroacetate

MS (ESI+): 482 (M+H)

Example 2521-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidemethanesulfonate

1-(4-Methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamide(208 mg) was dissolved in ethyl acetate (2 ml), a solution ofmethanesulfonic acid (401) in ethyl acetate (1 ml) was added at 75° C.,hexane (1 ml) was added, and the mixture was heated under reflux andstood at room temperature overnight. The precipitated crystals werecollected by filtration, and dried at 70° C. for 3 hr to give the objectproduct (158 mg).

MS (ESI+, m/e) 500 (M+1)

melting point: 144.4° C.

In the same manner as in Reference Example 22, the compound of ReferenceExample 448 was obtained.

Reference Example 448 tert-butyl(3S,5R)-3-[(cyclopropylmethyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 368 (M+1)

In the same manner as in Reference Example 64, the compound of ReferenceExample 449 was obtained.

Reference Example 449 tert-butyl(3S,5R)-3-[(1H-benzimidazol-2-ylcarbonyl)(cyclopropylmethyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 512 (M+1)

In the same manner as in Reference Example 69, the compounds ofReference Example 450 and Reference Example 451 were obtained.

Reference Example 450 tert-butyl (3S,5R)-3-[(cyclopropylmethyl){[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 598 (M+1)

Reference Example 451 tert-butyl (3S,5R)-3-[(cyclopropylmethyl){[1-(3-methoxypropyl)-1H-benzimidazol-2-yl]carbonyl}amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 584 (M+1)

In the same manner as in Example 12, the compounds of Example 253 andExample 254 were obtained.

Example 253N-(cyclopropylmethyl)-1-(4-methoxybutyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 498 (M+1)

Example 254N-(cyclopropylmethyl)-1-(3-methoxypropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 484 (M+1)

Reference Example 452 tert-butyl(3S,5R)-3-amino-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

tert-Butyl(3S,5R)-3-{[(benzyloxy)carbonyl]amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(39 g) and palladium(II) hydroxide-carbon (4 g) were suspended inmethanol (500 ml) and the mixture was stirred under a hydrogenatmosphere (1 atom) at room temperature for 15 hr. The palladiumcatalyst was filtered off, and the filtrate was concentrated underreduced pressure to give tert-butyl(3S,5R)-3-amino-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (28g).

¹H-NMR (CDCl₃) δ 1.41-1.52 (9H, m), 1.53-1.66 (3H, m), 2.03 (1H, d),2.36 (1H, d), 2.59-2.83 (3H, m), 3.45-3.76 (8H, m), 3.97-4.30 (2H, m).

MS (ESI+, m/e) 314 (M+1)

Reference Example 453 tert-butyl(3R,5S)-3-(morpholin-4-ylcarbonyl)-5-{[(2-nitrophenyl)sulfonyl]amino}piperidine-1-carboxylate

tert-Butyl(3S,5R)-3-amino-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (3.13g) and triethylamine (2.1 ml) were dissolved in THF (30 ml),2-nitrobenzenesulfonyl chloride (2.44 g) was added at room temperature,and the mixture was stirred at room temperature for 15 hr. Water wasadded to the reaction mixture, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure to give the object product (4.68 g).

¹H-NMR (CDCl₃) δ 1.43 (9H, s), 1.80-2.14 (2H, m), 2.55-2.98 (3H, m),3.36-3.77 (9H, m), 3.89-4.18 (2H, m), 6.16 (1H, br. s.), 7.70-7.79 (2H,m), 7.81-7.89 (1H, m), 8.13-8.21 (1H, m).

MS (ESI+, m/e) 499 (M+1)

Reference Example 454 tert-butyl(3R,5S)-3-(morpholin-4-ylcarbonyl)-5-{[(2-nitrophenyl)sulfonyl](propyl)amino}piperidine-1-carboxylate

tert-Butyl(3R,5S)-3-(morpholin-4-ylcarbonyl)-5-{[(2-nitrophenyl)sulfonyl]amino}piperidine-1-carboxylate(4.68 g) was dissolved in DMA (20 ml), cesium carbonate (9.18 g) and1-iodopropane (1.83 ml) were added, and the mixture was stirred at 60°C. for 4 hr. The reaction mixture was diluted with water, and extractedwith ethyl acetate. The extract was washed with saturated brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was subjected to silica gel column chromatography,and a fraction eluted with ethyl acetate-hexane (3:7-10:0) wasconcentrated under reduced pressure to give the object product (4.02 g).

¹H-NMR (CDCl₃) δ 0.87 (3H, t), 1.45 (9H, s), 1.49-1.73 (1H, m),1.85-2.03 (2H, m), 2.61-2.90 (3H, m), 3.19 (2H, t), 3.47-3.74 (9H, m),3.79-3.95 (1H, m), 4.04-4.23 (2H, m), 7.58-7.66 (1H, m), 7.66-7.75 (2H,m), 8.02-8.10 (1H, m).

MS (ESI+, m/e) 541 (M+1)

Reference Example 455 tert-butyl(3R,5S)-3-(morpholin-4-ylcarbonyl)-5-(propylamino)piperidine-1-carboxylate

tert-Butyl(3R,5S)-3-(morpholin-4-ylcarbonyl)-5-{[(2-nitrophenyl)sulfonyl](propyl)amino}piperidine-1-carboxylate(4.02 g) and lithium hydroxide monohydrate (1.56 g) were dissolved inDMF (20 ml), thioglycol acid (1.3 ml) was added at room temperature, andthe mixture was stirred for 2 days at room temperature. The reactionmixture was diluted with aqueous sodium bicarbonate, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The residue was subjected to basicsilica gel column chromatography, and a fraction eluted with ethylacetate-hexane (1:9-10:0) was concentrated under reduced pressure. Theresidue was diluted with 10% aqueous citric acid solution, and washedwith ethyl acetate. The aqueous layer was neutralized with aqueoussodium bicarbonate and extracted with ethyl acetate. The extract waswashed with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure to give the objectproduct (1.89 g).

¹H-NMR (CDCl₃) δ 0.92 (3H, t), 1.36-1.71 (13H, m), 2.05 (1H, d),2.26-2.95 (6H, m), 3.50-3.75 (8H, m), 3.96-4.46 (2H, m).

MS (ESI+, m/e) 356 (M+1)

Reference Example 456 tert-butyl(3S,5R)-3-[(1H-benzimidazol-2-ylcarbonyl)(propyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

2-(Trichloromethyl)-1H-benzimidazole (1.09 g) and tert-butyl(3R,5S)-3-(morpholin-4-ylcarbonyl)-5-(propylamino)piperidine-1-carboxylate(1.49 g) were dissolved in THF (120 ml), sodium hydrogen carbonate (3.52g) and water (60 ml) were added and the mixture was stirred at roomtemperature for 2 hr. The reaction mixture was diluted with aqueoussodium bicarbonate, and extracted with ethyl acetate. The extract waswashed with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wassubjected to basic silica gel column chromatography, and a fractioneluted with ethyl acetate-hexane (2:8-10:0) was concentrated underreduced pressure to give the object product (1.97 g).

¹H-NMR (CDCl₃) δ 0.88-1.06 (3H, m), 1.30-1.54 (9H, m), 1.59-1.91 (3H,m), 1.92-2.48 (2H, m), 2.68-3.21 (3H, m), 3.26-4.00 (9H, m), 4.01-4.56(3H, m), 7.28-7.45 (2H, m), 7.47-7.61 (1H, m), 7.60-7.89 (1H, m),10.43-11.17 (1H, m).

MS (ESI+, m/e) 500 (M+1)

Reference Example 457 tert-butyl(3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(propyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

tert-Butyl(3S,5R)-3-[(1H-benzimidazol-2-ylcarbonyl)(propyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(1.97 g) and 4-methoxybutyl methanesulfonate (754 mg) were dissolved inDMA (50 ml), cesium carbonate (1.93 g) was added and the mixture wasstirred at 60° C. for 15 hr. The reaction mixture was diluted withwater, and the mixture was extracted with ethyl acetate. The extract waswashed with brine, and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure. The residue was subjected tobasic silica gel column chromatography, and a fraction eluted with ethylacetate-hexane (0:10-5:5) was concentrated under reduced pressure togive the object product (2.19 g).

¹H-NMR (CDCl₃) δ 0.64-1.08 (3H, m), 1.29-1.53 (9H, m), 1.54-1.72 (3H,m), 1.75-2.40 (5H, m), 2.49-3.21 (5H, m), 3.22-3.90 (14H, m), 4.00-4.52(4H, m), 7.27-7.40 (2H, m), 7.45 (1H, t), 7.54-7.84 (1H, m).

MS (ESI+, m/e) 586 (M+1)

Example 2551-(4-methoxybutyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-N-propyl-1H-benzimidazole-2-carboxamidedihydrochloride

tert-Butyl(3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(propyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(2.19 g) was dissolved in 4M hydrogen chloride-ethyl acetate (20 ml),and the mixture was stirred at room temperature for 2 hr. The reactionmixture was concentrated to give the object product (2.09 g). ¹H-NMR(DMSO-d₆) δ 0.59-1.00 (3H, m), 1.38-1.88 (6H, m), 1.92-2.11 (2H, m),2.16-2.36 (1H, m), 2.85-3.88 (20H, m), 4.22-4.57 (3H, m), 7.24-7.44 (2H,m), 7.59-7.82 (2H, m), 8.46-9.94 (2H, m).

In the same manner as in Reference Example 22, the compound of ReferenceExample 458 was obtained.

Reference Example 458 tert-butyl(3S,5R)-3-[(1-methylethyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 356 (M+1)

In the same manner as in Reference Example 379, the compound ofReference Example 459 was obtained.

Reference Example 459 tert-butyl(3S,5R)-3-[{[1-(2-fluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(1-methylethyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 631 (M+1)

In the same manner as in Reference Example 219, the compound ofReference Example 460 was obtained.

Reference Example 460 tert-butyl(3S,5R)-3-[(1-methylethyl){[3-(phenoxymethyl)imidazo[1,2-a]pyridin-2-yl]carbonyl}amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 606 (M+1)

In the same manner as in Example 101, the compounds of Example 256 andExample 257 were obtained.

Example 2561-(2-fluorophenyl)-5-(4-methoxybutyl)-N-(1-methylethyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-1,2,3-triazole-4-carboxamidehydrochloride

MS (ESI+, m/e) 531 (M+1)

Example 257N-(1-methylethyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-3-(phenoxymethyl)imidazo[1,2-a]pyridine-2-carboxamidedihydrochloride

MS (ESI+, m/e) 506 (M+1)

In the same manner as in Reference Example 64, the compound of ReferenceExample 461 was obtained.

Reference Example 461 tert-butyl(3S,5R)-3-[(1H-benzimidazol-2-ylcarbonyl)(1-methylethyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 500 (M+1)

In the same manner as in Reference Example 69, the compound of ReferenceExample 462 was obtained.

Reference Example 462 tert-butyl(3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(1-methylethyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 586 (M+1)

In the same manner as in Example 101, the compound of Example 258 wasobtained.

Example 2581-(4-methoxybutyl)-N-(1-methylethyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 486 (M+1)

In the same manner as in Reference Example 379, the compound ofReference Example 463 was obtained.

Reference Example 463 tert-butyl(3S,5R)-3-[{[1-(2-fluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(propyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 631 (M+1)

In the same manner as in Reference Example 219, the compound ofReference Example 464 was obtained.

Reference Example 464 tert-butyl(3R,5S)-3-(morpholin-4-ylcarbonyl)-5-[{[3-(phenoxymethyl)imidazo[1,2-a]pyridin-2-yl]carbonyl}(propyl)amino]piperidine-1-carboxylate

MS (ESI+, m/e) 606 (M+1)

In the same manner as in Example 101, the compounds of Example 259 andExample 260 were obtained.

Example 2591-(2-fluorophenyl)-5-(4-methoxybutyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-N-propyl-1H-1,2,3-triazole-4-carboxamidehydrochloride

MS (ESI+, m/e) 531 (M+1)

Example 260N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-3-(phenoxymethyl)-N-propylimidazo[1,2-a]pyridine-2-carboxamidedihydrochloride

MS (ESI+, m/e) 506 (M+1)

In the same manner as in Reference Example 64, the compound of ReferenceExample 465 was obtained.

Reference Example 465 tert-butyl(3S,5R)-3-[(1H-benzimidazol-2-ylcarbonyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 458 (M+1)

In the same manner as in Reference Example 69, the compound of ReferenceExample 466 was obtained.

Reference Example 466 tert-butyl(3S,5R)-3-({[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}amino)-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 544 (M+1)

In the same manner as in Example 101, the compound of Example 261 wasobtained.

Example 2611-(4-methoxybutyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 444 (M+1)

Reference Example 467 tert-butyl(3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(methyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

tert-Butyl(3S,5R)-3-({[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}amino)-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate(290 mg) was dissolved in DMF (5 ml), sodium hydride (60% in oil) (880mg) was added, and the mixture was stirred at room temperature for 1 hr.Methyl iodide (98 μl) was added and the mixture was stirred at roomtemperature for 3 days. The reaction mixture was diluted with aqueoussodium bicarbonate, and the mixture was extracted with ethyl acetate.The extract was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The residue was subjected to basic silica gel column chromatography, anda fraction eluted with ethyl acetate-hexane (1:9-7:3) was concentratedunder reduced pressure to give the object product (225 mg).

MS (ESI+, m/e) 558 (M+1)

In the same manner as in Reference Example 467, the compound ofReference Example 468 was obtained.

Reference Example 468 tert-butyl(3S,5R)-3-(ethyl{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}amino)-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

MS (ESI+, m/e) 572 (M+1)

In the same manner as in Example 12, the compounds of Example 262 andExample 263 were obtained.

Example 2621-(4-methoxybutyl)-N-methyl-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 458 (M+1)

Example 263N-ethyl-1-(4-methoxybutyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidedihydrochloride

MS (ESI+, m/e) 472 (M+1)

Example 2641-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidehydrochloride

1-(4-Methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamide(24.4 g) was dissolved in ethyl acetate (225 ml), and the mixture washeated to 45-55° C. 4M Hydrogen chloride-ethyl acetate (12.8 ml) wasadded dropwise, and the precipitate was dissolved at the sametemperature. After confirmation of dissolution, heptane (75 ml) wasadded dropwise, and the mixture was cooled to 25-35° C. The seed crystal(45 mg) was added and the mixture was stirred for 30 min. The mixturewas heated to 50-55° C., and heptane (150 ml) was added dropwise. Themixture was stirred at the same temperature for 1 hr, gradually cooledto 0-5° C., and stirred at the same temperature for 1 hr. Theprecipitated crystals were collected by filtration, washed with ethylacetate-heptane (90 ml), and dried under reduced pressure at 40-50° C.to give the object product (15.3 g).

Example 2651-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidehydrochloride

1-(4-Methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamidehydrochloride (3.0 g) was suspended in 2-propanol-ethyl acetate (25.5ml), and dissolved by heating to 40-50° C. Heptane (10.5 ml) was addeddropwise at the same temperature, and the mixture was cooled to 30-40°C., and seed crystal (3.0 mg) was added. Heptane (7 ml) was addeddropwise at the same temperature, and the mixture was heated to 45-50°C. 2-Propanol-ethyl acetate-heptane (12 ml) was added dropwise, heptane(9 ml) was further added dropwise, and the mixture was heated to 50-60°C. and stirred for 1 hr. The mixture was cooled to 5° C. or lower, andstirred at the same temperature for 1 hr. The crystals were collected byfiltration, washed with ethyl acetate-heptane (15 ml) cooled to 5° C. orlower, and dried under reduced pressure at 40-50° C. to give the objectproduct (2.6 g).

MS (ESI+, m/e) 500 (M+1)

melting point: 158° C.

Preparation Example 1

(1) compound of Example 1 10.0 g (2) Lactose 70.0 g (3) Corn starch 50.0g (4) Soluble starch  7.0 g (5) Magnesium stearate  3.0 g

10.0 g of the compound of Example 1 and 3.0 g of magnesium stearate aregranulated with 70 ml of an aqueous solution of soluble starch (7.0 g assoluble starch), then and the mixture is dried and mixed with 70.0 g oflactose and 50.0 g of corn starch (any of lactose, corn starch, solublestarch and magnesium stearate is products in conformity to the 14^(th)revision of the Japanese Pharmacopoeia). The mixture is compressed togive tablets.

Experimental Example 1

Human renin was obtained by expressing preprorenin (1-406) in an animalcell, treating the prorenin (24-406) contained in the culturesupernatant with trypsin, and taking the active type (67-406).

(1) Construction of Renin-Expressing Vector

A plasmid DNA to express human renin in HEK293 cells was prepared asfollows. PCR was carried out using human renal cDNA (ClontechLaboratories, Inc., Marathon Ready cDNA) as the template and using twosynthetic DNAs (5′-AAGCTTATGGATGGATGGAGA-3′; SEQ ID No.1, and5′-GGATCCTCAGCGGGCCAAGGC-3′; SEQ ID No.2), and the obtained fragmentswere cloned using a TOPO TA Cloning Kit (Invitrogen Corp.). The obtainedfragments were subcloned into pcDNA3.1(+) that had been cleaved byHindIII and BamHI, thus to obtain a plasmid DNA for human preproreninexpression (pcDNA3.1(+)/hREN).

(2) Construction of Angiotensinogen-Expressing Vector

A plasmid DNA to express human angiotensinogen in HEK293 cells wasprepared as follows. PCR was carried out using human liver cDNA(Clontech Laboratories, Inc., Marathon Ready cDNA) as the template andusing two synthetic DNAs (5′-AAGCTTATGCGGAAGCGAGCACCCCAGTCT-3′; SEQ IDNo.3, and5′-GGATCCTCACTTGTCATCGTCGTCCTTGTAGTCTGCTGTGCTCAGCGGGTTGGCCACGC-3′; SEQID No.4), and the obtained fragments were cloned using a TOPO TA CloningKit (Invitrogen Corp.). The obtained fragments were subcloned intopcDNA3.1(+) that had been cleaved by HindIII and BamHI, thereby to givea plasmid DNA for expression of human angiotensinogen having a FLAGtagon the C-terminal (pcDNA3.1(+)/hAngiotensinogen-FLAG). Then, PCR wascarried out using the pcDNA3.1(+)/hAngiotensinogen-FLAG as the templateand using two synthetic DNAs(5′-CCTTAAGCTTCCACCATGCGGAAGCGAGCACCCCAGTCT-3′; SEQ ID No.5, and5′-TTGGATCCTCATGCTGTGCTCAGCGGGTTGGCCACGCGG-3′; SEQ ID No.6), and theobtained fragments were cloned using a TOPO TA Cloning Kit (InvitrogenCorp.). The obtained fragments were subcloned into pcDNA3.1(+) that hadbeen cleaved by HindIII and BamHI, thus to obtain a plasmid DNA forhuman angiotensinogen expression (pcDNA3.1(+)/hAngiotensinogen).

(3) Expression of Preprorenin and Purification of Prorenin (24-406)

Expression of human preprorenin was conducted using FreeStyle 293Expression System (Invitrogen Corp.). According to the manualaccompanying the FreeStyle 293 Expression System, the plasmid DNA forhuman preprorenin expression (pcDNA3.1(+)/hREN) constructed in theabove-mentioned (1) was used to conduct transient expression byFreeStyle 293-F cells. After transfection of the plasmid DNA, the cellswere subjected to shaking culture under the conditions of 37° C., 8% CO₂and 125 rpm for 3 days. A 600-ml aliquot of the culture medium wascentrifuged at 2,000 rpm for 10 min to recover the culture supernatantcontaining prorenin (24-406). The culture supernatant was concentratedby ultrafiltration using a PM10 membrane (Millipore, Inc.) to a volumeof about 50 ml, and then was dialyzed against 20 mM Tris-hydrochloricacid (pH 8.0). The dialyzate was fed to a 6-ml RESOURCE Q column (GEHealthcare) equilibrated with 20 mM Tris-hydrochloric acid (pH 8.0) at aflow rate of 3 ml/min to adsorb the prorenin (24-406). After washing thecolumn with the buffer solution used in the equilibration, elution wascarried out by means of a linear concentration gradient of sodiumchloride from 0 M to 0.4 M. The fractions containing prorenin (24-406)were collected and concentrated using Vivaspin 20 (molecular weight cutoff 10,000; Vivascience, Inc.) to a volume of about 2 ml.

The concentrated liquid was subjected to gel filtration chromatographyusing HiLoad 16/60 Superdex 200 pg (GE Healthcare) equilibrated with 20mM Tris-hydrochloric acid (pH 8.0) containing 0.15 M sodium chloride, ata flow rate of 1.4 ml/min, thus to obtain 3.6 mg of purified prorenin(24-406).

(4) Purification of Active Type Renin (67-406)

To 3.6 mg of prorenin (24-406) dissolved in 5.2 ml of 0.1 MTris-hydrochloric acid (pH 8.0), 12 g of trypsin (Roche DiagnosticsCorp.) was added, and the mixture was allowed to react at 28° C. for 55min to carry out activation of renin. After the reaction, 0.4 ml ofimmobilized trypsin inhibitor (Pierce Biotechnology, Inc.) was added toremove the trypsin used in the activation by adsorption. The reactionliquid containing the active type renin was concentrated using Vivaspin20 (molecular weight cut off 10,000, Vivascience, Inc.), and was dilutedwith 20 mM Tris-hydrochloric acid (pH 8.0). The diluted liquid was fedto a TSKgel DEAE-5PW column (7.5 mm I.D.×75 mm, Tosoh Corp.)equilibrated with 20 mM Tris-hydrochloric acid (pH 8.0) at a flow rateof 1 ml/min to adsorb the active type renin (67-406). The column waswashed with the buffer solution used for the equilibration, and thenelution was carried out by means of a sodium chloride linearconcentration gradient from 0 M to 0.3 M, thus to obtain 1.5 mg of apurified product of active type renin (67-406).

(5) Purification of Angiotensinogen

Expression of human angiotensinogen was conducted using FreeStyle 293Expression System (Invitrogen Corp.). According to the manualaccompanying the FreeStyle 293 Expression System, the plasmid DNA forhuman angiotensinogen expression (pcDNA3.1(+)/hAngiotensinogen)constructed in the above-mentioned (2) was used to conduct transientexpression by FreeStyle 293-F cells. After transfection of the plasmidDNA, the cells were subjected to shaking culture under the conditions of37° C., 8% CO₂ and 125 rpm for 3 days. A 600-ml aliquot of the culturemedium was centrifuged at 2,000 rpm for is 10 min to recover the culturesupernatant containing angiotensinogen. To the culture supernatant wasadded ammonium sulfate (30% saturated concentration), and the mixturewas thoroughly stirred and centrifuged at 8,000 rpm for 20 min. Theobtained supernatant was added to TOYO Pearl butyl 650M (2×5 cm, TosohCorporation) equilibrated with 50 mM tris-hydrochloric acid (pH 8.0)containing 30% saturated ammonium sulfate, at a flow rate of 25 ml/minto allow adsorption. After washing with equilibration buffer,angiotensinogen was eluted by linear concentration gradient from thebuffer used for equilibration to 20 mM tris-hydrochloric acid (pH 8.0).The eluate containing angiotensinogen was applied to repeatedconcentration and dilution using Vivaspin 20 (molecular weight cut off10,000, Vivascience, Inc.), and the buffer was changed to 20 mMtris-hydrochloric acid (pH 8.0). The eluate was fed to a 6-ml RESOURCE Qcolumn (Amersham Biosciences, Inc.) equilibrated with 20 mMTris-hydrochloric acid (pH 8.0) containing 50 mM sodium chloride at aflow rate of 6 ml/min to adsorb the angiotensinogen. After washing thecolumn with the buffer solution used in the equilibration, elution wascarried out by means of a linear concentration gradient of sodiumchloride from 50 mM to 400 mM. The fractions containing angiotensinogenwere collected and concentrated using Vivaspin (molecular weight cut off10,000, Vivascience, Inc.) to a volume of about 2 ml. The concentratedliquid was subjected to gel filtration chromatography using HiLoad 26/60Superdex 200 pg (GE Healthcare) equilibrated with 20 mMTris-hydrochloric acid (pH 8.0) containing 0.15 M sodium chloride, at aflow rate of 2.0 ml/min, thus to obtain 7.0 mg of purifiedangiotensinogen.

(6) Measurement of Renin Inhibition Value

As a substrate for renin activity measurement, the angiotensinogenmentioned in (5) above was used. 11 each of the test compound(containing 100% DMSO) was added to each well of a 384-well plate(ABgene). Renin was diluted with a buffer solution for reaction (20 mMsodium phosphate (pH 7.4)) to a concentration of 57 μM, and 14 μl eachof the dilution was added to each well. The dilution was left to standat 37° C. for min, and then 5 μl of each of a 6 μM solution of substrateangiotensinogen was added to each well to initiate the reaction. Thereaction mixture was left to stand at 37° C. for min, and then 20 μleach of a reaction terminating solution [20 mM Tris-hydrochloric acid(pH 7.4), 150 mM sodium chloride, 0.1% BSA, 0.05% Tween 20 and 1 μMCGP-29287] was added to each well to terminate the reaction, thus anenzyme reaction solution was obtained. The amount of angiotensin Iproduced by an enzyme reaction was quantified by Enzyme Immuno Assay(EIA) described below.

Anti-angiotensin I antibody (Peninsula Laboratories Inc.) diluted5.000-fold with PBS was added to each well of a 384 well black plate(Nalge Nunc International Co., Ltd.) by 25 μl, and left standingovernight at 4° C. to immobilize the antibody in the plate. The antibodysolution was removed, PBS solution (100 μl) containing 1% BSA was addedto each well, and the mixture was left standing at room temperature for2 hr for blocking. The blocking solution was removed, and each well waswashed 5 times with 100 μl of 0.05% Tween20-PBS. An angiotensin Istandard solution (Wako Pure Chemical Industries, Ltd.) prepared to0.156-10 nM with an enzyme reaction solution or buffer [20 mMtris-hydrochloric acid (pH 7.4), 150 mM sodium chloride, 0.1% BSA, 0.05%Tween20] was dispensed to each well by 10 μl. Then, a biotinatedangiotensin I solution (AnaSpec, 15 μl) prepared to 1.6 nM with a buffer[20 mM tris-hydrochloric acid (pH 7.4), 150 mM sodium chloride, 0.01%BSA, 0.05% Tween20] was added to each well, mixed with a plate mixer andleft standing at room temperature for 1 hr. The solutions were removedfrom each well, and each well was washed 5 times with 100 μl of 0.05%Tween20-PBS. Horseradish peroxydase Streptavidin (PIERCE Biotecnologyinc., 25 μl) diluted to 100 ng/ml with a buffer [20 mM tris-hydrochloricacid (pH 7.4), 150 mM sodium chloride, 0.1% BSA, 0.05% Tween 20] wasadded to each well and the mixture was left standing at room temperaturefor 30 min. The solutions were removed from each well, and each well waswashed 5 times with 100 μl of 0.05% Tween20-PBS. SuperSignal ELISA femtoMaximum Sensitivity Substrate (PIERCE Biotecnology Inc.) was added by 25μl and luminescence intensity was measured by EnVision (Perkin ElmerInc.). An analytical curve was drawn from the luminescence intensity ofwells containing an angiotensin I standard solution, and the amount ofangiotensin I produced by an enzyme reaction was calculated and used asan index of renin activity.

While the reaction rate of the well where 100% DMSO only was added wastaken as 0% inhibition rate, and the reaction rate of the well whereangiotensin I was not contained was taken as 100% inhibition rate, therenin inhibitory activity of the wells where the test compound(containing 100% DMSO) was added was calculated.

(7) Results

The results measured according to the above-mentioned method (6) areshown in Table 1.

TABLE 1 Human renin inhibitory activity inhibitory activity Example No.(%) at 0.1 μM  3 96  4 96  10 97  12 97  25 98  38 98  40 97  48 97  4997  73-1 96  73-2 96  74-1 94  74-2 96  75-1 95  75-2 90  85 97 117 98233 97 235 97

From the results of Table 1, it is clear that compounds (I) and (II) ofthe present invention have a superior renin inhibitory activity.

Experimental Example 2

(1) Ex Vivo Renin Inhibitory Activity Test Using Macaca fascicularis

Male macaca fascicularis was used. The blood samples were collected fromfemoral vein at the time points of before drug administration and 4 hrafter drug administration (EDTA-2Na⁺ at final concentration of 7.5mmol/L was used as an anticoagulant). The collected blood wascentrifuged using a cooling centrifuge (centrifuge 5415R: Eppendorf Co.,Ltd.) at 4° C., 10000 rpm for 10 min, and the obtained plasma waspreserved at −20° C. until a parameter measurement. The drug wasdissolved in 0.5% methylcellulose and orally administered at 1 mg/kg.The plasma renin activity (PRA) was measured using RIA kit (reninactivity “PRA”: SRL Inc.). PRA was calculated by the following formula.

${P\; R\;{A\left( {{ng}\text{/}{mL}\text{/}h} \right)}} = \frac{\left( {X_{37}{{\,^{{^\circ}}\mspace{11mu} C}.{- X_{4}}}{{\,^{{^\circ}}\mspace{11mu} C}.}} \right)}{{incubation}\mspace{14mu}{time}\mspace{14mu}(h)}$

X₃₇° C.: angiotensin I concentration for incubation at 37° C.

X₄° C.: angiotensin I concentration for incubation at 4° C.

PRA at each time point after drug administration was calculated aspercentage relative to the value before administration and taken as PRA%. The renin inhibitory activity of the drug administration group wascalculated as an inhibitory rate by amending the PRA % at each timepoint after drug administration with PRA % of the vehicle group.

(2) Results

The results measured according to the above-mentioned method (1) areshown in Table 2.

TABLE 2 Macaca fascicularis plasma renin activity PPA inhibitoryactivity Example (%, n = 3-7) Example 7 93 Example 10 72 Example 11 89Example 18 89 Example 21 85 Example 25 79 Example 33 77 Example 40 75Example 42 70 Example 48 78 Example 60 85 Example 62 75 Example 73-1 77Example 73-2 90 Example 74-1 90 Example 74-2 54 Example 75-1 86 Example75-2 71 Example 76 79 Example 233 67 Example 235 62 Example 253 77Example 255 84

From the results of Table 2, it is clear that compounds (I) and (II) ofthe present invention show a sustained and superior renin inhibitoryactivity in the plasma of Macaca fascicularis that received drugadministration.

[Sequence Listing Free Text]

[SEQ ID NO: 1] primer

[SEQ ID NO: 2] primer

[SEQ ID NO: 3] primer

[SEQ ID NO: 4] primer

[SEQ ID NO: 5] primer

[SEQ ID NO: 6] primer

[SEQ ID NO: 7] partial sequence of human angiotensinogen

[SEQ ID NO: 8] substrate peptide of renin

INDUSTRIAL APPLICABILITY

Compound (I) and compound (II) have superior renin inhibitory activityand thus are useful as agents for the prophylaxis or treatment ofhypertension, various organ is damages attributable to hypertension, andthe like.

This application is based on patent application Nos. 161049/2008 and004882/2009 filed in Japan, the contents of which are herebyincorporated by reference.

The invention claimed is:
 1. A compound represented by formula (I):

wherein R¹ is a hydrogen atom, an alkyl group optionally havingsubstituent(s), an alkenyl group optionally having substituent(s) or acycloalkyl group optionally having substituent(s); R² is a grouprepresented by the formula: —CO—NR′R″, wherein R′ and R″ together withthe nitrogen atom bonded thereto form morpholine optionally having 1 to3 substituents selected from halogen atom(s); X is (1) a hydrogen atom;(2) a C₁₋₆ alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of (a) a halogen atom, (b) a hydroxygroup, (c) a C₁₋₆ alkoxy group optionally having a C₁₋₆ alkoxy group ora halogen atom, (d) a C₁₋₆ alkylthio group, (e) an aryl group, (f) anaryloxy group optionally having a C₁₋₆ alkoxy group or a halogen atom,and (g) a heteroaryl group; or (3) a C₃₋₁₀ cycloalkyl group; and ring Ais benzimidazole, or a salt thereof.
 2. A compound represented byformula (II):

wherein R¹ is a hydrogen atom, an alkyl group optionally havingsubstituent(s), an alkenyl group optionally having substituent(s) or acycloalkyl group optionally having substituent(s); R³ is an alkyl group,an alkenyl group optionally having substituent(s), a cycloalkyl groupoptionally having substituent(s), an alkylthio group optionally havingsubstituent(s), an alkylsulfinyl group optionally having substituent(s),an alkylsulfonyl group optionally having substituent(s), an alkoxy groupoptionally having substituent(s), an aryl group optionally havingsubstituent(s) or a heteroaryl group optionally having substituent(s);X¹ is a C₁₋₆ alkylene group; ring A¹ is benzimidazole; and ring B is aring represented by

wherein R⁴ is a group represented by the formula: —CO—NR′R″, wherein R′and R″ together with the nitrogen atom bonded thereto form morpholineoptionally having 1 to 3 substituents selected from halogen atom(s), ora salt thereof.
 3. The compound of claim 1, wherein R¹ is a C₁₋₆ alkylgroup optionally having substituent(s).
 4. The compound of claim 2,wherein R¹ is a C₁₋₆ alkyl group optionally having substituent(s). 5.The compound of claim 1, wherein X is a C₁₋₆ alkyl group optionallysubstituted by a C₁₋₆ alkoxy group.
 6. The compound of claim 2, whereinR³ is a C₁₋₆ alkoxy group optionally having substituent(s). 7.1-(4-Hydroxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamideor a salt thereof. 8.1-(4-Methoxybutyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-N-propyl-1H-benzimidazole-2-carboxamideor a salt thereof.
 9. A pharmaceutical composition comprising thecompound of claim 1, or salt thereof, and a pharmaceutically acceptablecarrier.
 10. A pharmaceutical composition comprising the compound ofclaim 2, or a salt thereof, and a pharmaceutically acceptable carrier.11. A method for the treatment of hypertension in a mammal comprisingadministering a therapeutically effective amount of the compound ofclaim 1 or salt thereof to the mammal.
 12. A method for the treatment ofhypertension in a mammal comprising administering a therapeuticallyeffective amount of the compound of claim 2 or salt thereof to themammal.